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Abstract
Biomaterials with dual functions of osteoimmunomodulation and bone repair are very promising in the field of orthopedic materials. For this purpose, we prepared a copper-based carbon dots (CuCDs) and doped...
Glioblastoma multiforme (GBM) is one of the most lethal malignant brain tumors in the central nervous system. Patients face many challenges after surgery, including tumor recurrence, intracranial pressure increase due to cavitation, and limitations associated with immediate postoperative oral chemotherapy. Here an injected peptide gel with in situ immunostimulatory functions is developed to coordinate the regulation of glutamine metabolism and chemodynamic therapy for overcoming these postoperative obstacles. The methodology entails crafting injectable gel scaffolds with short peptide molecules, incorporating the glutaminase inhibitor CB‐839 and copper peptide self‐assembled particles (Cu‐His NPs) renowned for their chemodynamic therapy (CDT) efficacy. By fine‐tuning glutamic acid production via metabolic pathways, this system not only heightens the therapeutic prowess of copper peptide particles in CDT but also escalates intracellular oxidative stress. This dual mechanism culminates in augmented immunogenic cell death within glioblastoma multiforme cells and improves a conducive immune microenvironment. Based on the concept of metabolic reprogramming, this treatment strategy has great potential to significantly reduce GBM tumor recurrence and prolong median survival in murine models.
Since the diseases that cause bone defects are mostly inflammatory diseases, the current bone grafts are unable to effectively regulate osteoimmune activity, leading to the impaired osteogenesis and unfavorable bone regeneration. In this study, inspired by bone composition, biomimetic mesoporous bioactive glass nanoparticle (MBG)/bovine serum albumin (BSA) bone grafts are designed for inflammatory bone defects. Systematically, MBG/BSA bone grafts are evaluated for characterization, bioactivity, anti‐inflammatory, antioxidant activity, and osteogenic activity. MBG/BSA bone grafts are proved to be biocompatible and can release bioactive ions including calcium and silicon in a sustained manner. Furthermore, MBG/BSA reprograms the macrophage phenotype toward anti‐inflammation that is beneficial for bone regeneration. The antioxidative activity is also validated under inflammation and the mechanism may be via the interleukin‐4 (IL‐4)/Signal transducer and activator of transcription 6 (STAT6) pathway. The osteogenic differentiation and mineralization are also facilitated due to the improved immunoregulation of MBG/BSA. Overall, this work suggests that the MBG/BSA bone grafts with improved immunomodulatory properties are an ideal material for inflammatory bone regeneration application.
Osteochondral (OC) defects pose an enormous challenge with no entirely satisfactory repair strategy to date. Herein, a 3D printed gradient hydrogel scaffold with a similar structure to that of OC tissue is designed, involving a pure hydrogel‐based top cartilage layer, an intermediate layer for calcified cartilage with 40% (w w−1) nanohydroxyapatite (nHA) and 60% (w w−1) hydrogel, and a 70/30% (w w−1) nHA/hydrogel‐based bottom subchondral bone layer. This study is conducted to evaluate the efficacy of the scaffold with nHA gradients in terms of its ability to promote OC defect repair. The fabricated composites are evaluated for physicochemical, mechanical, and biological properties, and then implanted into the OC defects in 56 rats. Overall, bone marrow stromal cells (BMSCs)‐loaded gradient scaffolds exhibit superior repair results as compared to other scaffolds based on gross examination, micro‐computed tomography (micro‐CT), as well as histologic and immunohistochemical analyses, confirming the ability of this novel OC graft to facilitate simultaneous regeneration of cartilage‐subchondral bone. A 3D printed nanohydroxyapatite/hydrogel composite with a gradient structure that closely matches the cartilage‐subchondral bone is prepared. With such a 3‐layer gradient structure, the scaffold can exactly match the biomedical functions of the cartilage, calcified cartilage, and subchondral bone, meanwhile, possessing desired dimensional stability, porous microstructure, remarkable mechanical properties, appropriate degradability, and optimal in vivo repair outcomes.
Development of high-performance carbon dots (CDs) with emission wavelength longer than 660 nm (deep red emission) is critical in deep-tissue bioimaging, yet it is still a major challenge to obtain CDs with both narrow full width at half maximum (FWHM) and high deep red/near-infrared emission yield. Here, deep red emissive carbonized polymer dots (CPDs) with unprecedented FWHM of 20 nm are synthesized. The purified CPDs in dimethyl sulfoxide (DMSO) solution possess quantum yield (QY) as high as 59% under 413 nm excitation, as well as recorded QY of 31% under 660 nm excitation in the deep red fluorescent window. Detailed characterizations identify that CPDs have unique polymer characteristics, consisting of carbon cores and the shells of polymer chains, and π conjugated system formed with N heterocycles and aromatic rings govern the single photoluminescence (PL) center, which is responsible for high QY in deep red emissive CPDs with narrow FWHM. The CPDs exhibit strong absorption and emission in the deep red light region, low toxicity, and good biocompatibility, making them an efficient probe for both one-photon and two-photon bioimaging. CPDs are rapidly excreted via the kidney system and hepatobiliary system.
Synthetic osteo‐promoting materials that are able to stimulate and accelerate bone formation without the addition of exogenous cells or growth factors represent a major opportunity for an aging world population. A co‐assembling system that integrates hyaluronic acid tyramine (HA‐Tyr ), bioactive peptide amphiphiles (GHK‐Cu2+), and Laponite (Lap ) to engineer hydrogels with physical, mechanical, and biomolecular signals that can be tuned to enhance bone regeneration is reported. The central design element of the multicomponent hydrogels is the integration of self‐assembly and enzyme‐mediated oxidative coupling to optimize structure and mechanical properties in combination with the incorporation of an osteo‐ and angio‐promoting segments to facilitate signaling. Spectroscopic techniques are used to confirm the interplay of orthogonal covalent and supramolecular interactions in multicomponent hydrogel formation. Furthermore, physico‐mechanical characterizations reveal that the multicomponent hydrogels exhibit improved compressive strength, stress relaxation profile, low swelling ratio, and retarded enzymatic degradation compared to the single component hydrogels. Applicability is validated in vitro using human mesenchymal stem cells and human umbilical vein endothelial cells, and in vivo using a rabbit maxillary sinus floor reconstruction model. Animals treated with the HA‐Tyr‐HA‐Tyr‐GHK‐Cu2+ hydrogels exhibit significantly enhanced bone formation relative to controls including the commercially available Bio‐Oss.
Despite the various synthesis methods to obtain carbon dots (CDs), the bottom‐up methods are still the most widely administrated route to afford large‐scale and low‐cost synthesis. However, as CDs are developed with increasing reports involved in producing many CDs, the structure and property features have changed enormously compared with the first generation of CDs, raising classification concerns. To this end, a new classification of CDs, named carbonized polymer dots (CPDs), is summarized according to the analysis of structure and property features. Here, CPDs are revealed as an emerging class of CDs with distinctive polymer/carbon hybrid structures and properties. Furthermore, deep insights into the effects of synthesis on the structure/property features of CDs are provided. Herein, the synthesis methods of CDs are also summarized in detail, and the effects of synthesis conditions of the bottom‐up methods in terms of the structures and properties of CPDs are discussed and analyzed comprehensively. Insights into formation process and nucleation mechanism of CPDs are also offered. Finally, a perspective of the future development of CDs is proposed with critical insights into facilitating their potential in various application fields. The classification of carbon dots (CDs) is improved and carbonized polymer dots (CPDs) are revealed with distinctive polymer/carbon hybrid structures and properties, as a new classification of CDs. The synthesis methods of CDs and effects of synthesis on the structures and properties of CPDs are discussed. Furthermore, insights are offered into the nucleation mechanism and the future development of CPDs.
Osteoarthritis (OA) is a common joint degenerative disease that causes pain, joint damage, and dysfunction. External hyaluronic acid (HA) supplement is a common method for the management of osteoarthritis which requires multi‐injections. It is demonstrated that biodegradable mesoporous silica nanoparticles successfully deliver an enzyme, hyaluronan synthase type 2 (HAS2), into synoviocytes from the temporomandibular joint (TMJ) and generate endogenous HA with high molecular weights. In a rat TMJ osteoarthritis inflammation model, this strategy promotes endogenous HA production and inhibits the synovial inflammation of OA for more than 3 weeks with one‐shot administration. Such nanotherapy also helps repairing the bone defects in a rat OA bone defect model. Engineered nanoparticles are applied to deliver hyaluronan synthase 2 into synoviocytes of temporomandibular joint for the management of osteoarthritis. Endogenous hyaluronan production is therefore promoted and the synovial inflammation of osteoarthritis inhibited for more than 3 weeks with one‐shot administration.
Osteoarthritis not only results in cartilage lesion, but also is accompanied with subchondral bone damage caused by the inflammatory response. It is of great significance to treat osteoarthritis by regulating the immune response. As copper (Cu) plays an essential role in immune response and anti-arthritis, a copper-incorporated bioactive glass-ceramics (Cu-BGC) may achieve the aim of healing cartilage lesion and reducing inflammatory response caused by osteoarthritis. We hypothesized that the Cu²⁺ released from Cu-BGC scaffolds may satisfy the requirements of cartilage regeneration and anti-arthritis.
Methods: 3D-printing method was employed to prepare Cu-BGC scaffolds. The stimulating effect on the chondrocytes and macrophages cultured with Cu-BGC extracts was investigated. Furthermore, the in vivo regenerative effect of Cu-BGC scaffolds on osteochondral defects was studied.
Results: The incorporation of Cu²⁺ into BGC considerably promoted the proliferation and maturation of chondrocytes, and induced macrophages shifting to anti-inflammatory phenotype. Histological analysis demonstrated that the Cu-BGC scaffolds meaningfully improved the regeneration of cartilage and elevated the recovery of the osteochondral interface as compared with the CTR and BGC groups. The potential mechanism is related to Cu²⁺ ions triggering the immune response of cartilage via activating HIF signaling pathway and inhibiting the inflammatory response in osteochondral tissue.
Conclusion: These results demonstrated that Cu-BGC scaffolds significantly facilitated the regeneration of cartilage and osteochondral interface, as well as inhibited inflammatory response, which may prevent the development of osteoarthritis associated with osteochondral defects.
Recently, strong polymer‐based hydrogels have been intensively investigated. However, the development of tough protein hydrogels with controlled degradation for bone regeneration has rarely been reported. Here, regenerated silk fibroin/gelatin (RSF/G) hydrogels with both strength and controlled degradation are prepared via physically and chemically double‐crosslinked networks. As a representative example, the 9%RSF/3%G hydrogel shows approximately 80% elongation and a compressive and tensile modulus of up to 0.25 and 0.21 MPa, respectively. It also shows a degradation rate that can be adjusted to approximately three months in vivo, a value between that of the rapidly degrading gelatin hydrogel and the slowly degrading RSF hydrogel. The 9%RSF/3%G hydrogel has good biocompatibility and promotes the proliferation and differentiation of bone marrow–derived stem cells compared with the control and pure RSF hydrogels. At 12 weeks after implantation of the gel in a calvarial defect, micro‐computed tomography shows greater bone volume and bone mineral density in the 9%RSF/3%G group. More importantly, histology reveals more mineralization and enhancements in the quality and rate of bone regeneration with less of a tissue response in the 9%RSF/3%G group. These results indicate the promising potential of this tough protein hydrogel with controlled degradation for bone regeneration applications. A novel facile strategy is developed to fabricate strong and tough hydrogels with controlled degradation by immersing an enzymatically crosslinked regenerated silk fibroin/gelatin (RSF/G) hydrogel in a salt solution, forming a double‐crosslinked network. The resulting 9%RSF/3%G hydrogel shows high strength, good biocompatibility, a suitable degradation rate, and capacity for promoting osteogenic differentiation and bone regeneration.
Statement of significance:
The study of implantable materials' interaction with biological systems occurs nearly exclusively in healthy cell and animal models. However, 15% of the US population smokes cigarettes, which is known to modulate immune response and tissue regeneration. To explore this interaction, we created a method of capturing smoke compounds as CSE for in vivo and in vitro use. We found chronic injection into mice produced an osteoporotic, pro-inflammatory phenotype similar to direct smoke models. Furthermore, CSE attenuated osteogenic differentiation and promoted a pro-inflammatory profile in MSCs and macrophages, respectively, when cultured on titanium surfaces. These results demonstrate that this CSE model may be useful for predicting how chronic tobacco exposure may adversely affect the outcome of biomedical implants in pre-clinical models.
Bone biomaterials play a vital role in bone repair by providing the necessary substrate for cell adhesion, proliferation, and differentiation and by modulating cell activity and function. In past decades, extensive efforts have been devoted to developing bone biomaterials with a focus on the following issues: (1) developing ideal biomaterials with a combination of suitable biological and mechanical properties; (2) constructing a cell microenvironment with pores ranging in size from nanoscale to submicro- and microscale; and (3) inducing the oriented differentiation of stem cells for artificial-to-biological transformation. Here we present a comprehensive review of the state of the art of bone biomaterials and their interactions with stem cells. Typical bone biomaterials that have been developed, including bioactive ceramics, biodegradable polymers, and biodegradable metals, are reviewed, with an emphasis on their characteristics and applications. The necessary porous structure of bone biomaterials for the cell microenvironment is discussed, along with the corresponding fabrication methods. Additionally, the promising seed stem cells for bone repair are summarized, and their interaction mechanisms with bone biomaterials are discussed in detail. Special attention has been paid to the signaling pathways involved in the focal adhesion and osteogenic differentiation of stem cells on bone biomaterials. Finally, achievements regarding bone biomaterials are summarized, and future research directions are proposed.
Bone is a richly vascularized connective tissue. As the main source of oxygen, nutrients, hormones, neurotransmitters and growth factors delivered to the bone cells, vasculature is indispensable for appropriate bone development, regeneration and remodeling. Bone vasculature also orchestrates the process of hematopoiesis. Blood supply to the skeletal system is provided by the networks of arteries and arterioles, having distinct molecular characteristics and localizations within the bone structures. Blood vessels of the bone develop through the process of angiogenesis, taking place through different, bone-specific mechanisms. Impaired functioning of the bone blood vessels may be associated with the occurrence of some skeletal and systemic diseases, i.e., osteonecrosis, osteoporosis, atherosclerosis or diabetes mellitus. When a disease or trauma-related large bone defects appear, bone grafting or bone tissue engineering-based strategies are required. However, a successful bone regeneration in both approaches largely depends on a proper blood supply. In this paper, we review the most recent data on the functions, molecular characteristics and significance of the bone blood vessels, with a particular emphasis on the role of angiogenesis and blood vessel functioning in bone development and regeneration, as well as the consequences of its impairment in the course of different skeletal and systemic diseases.
Statement of significance:
Nowadays, BCPs are definitely considered as the gold standard of bone substitutes in bone reconstructive surgery. Among the numerous clinical studies in literature demonstrating the performance of BCP, Passuti et al and Randsford et al studies largely contributed to the emergence of the BCPs. It could be interesting to come back to the main events that made their success and could explain their large adhesion from scientists to clinicians. This paper aims to review the most significant biological responses reported in the last 30 years, of these BCP-based materials. We also discuss about their exciting future applications as osteoconductive scaffold for delivering various bioactive molecules or bone cells in bone tissue engineering and regenerative medicine.
Statement of significance:
Biphasic calcium phosphates (BCPs) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalium Phosphate (β-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surgery. Doping can advantageously be used to improve their biological behaviors and/or magnetic properties; however, it is important to describe the doping mechanism of BCP thoroughly in order to fully appraise the benefit of the doping process. The present paper scrutinizes in detail the incorporation of ferric cation in order to correctly interpret the behavior of the iron-doped bioceramic in biological fluid. The temperature dependent mechanism has been fully described for the first time. And it clearly appears that temperature can be used to design the doping according to desired medical application: blood compatibility, remineralization, bactericidal or magnetic response.
Although copper (Cu) is recognized as an essential trace element, uncertainties remain regarding Cu reference values for humans, as illustrated by discrepancies between recommendations issued by different national authorities. This review examines human studies published since 1990 on relationships between Cu intake, Cu balance, biomarkers of Cu status, and health. It points out several gaps and unresolved issues which make it difficult to assess Cu requirements. Results from balance studies suggest that daily intakes below 0.8mg/d lead to net Cu losses, while net gains are consistently observed above 2.4mg/d. However, because of an incomplete collection of losses in all studies, a precise estimation of Cu requirements cannot be derived from available data. Data regarding the relationship between Cu intake and potential biomarkers are either too preliminary or inconclusive because of low specificity or low sensitivity to change in dietary Cu over a wide range of intakes. Results from observation and intervention studies do not support a link between Cu and a risk of cardiovascular disease, cognitive decline, arthritis or cancer for intakes ranging from 0.6 to 3mg/d, and limited evidence exists for impaired immune function in healthy subjects with a very low (0.38mg/d) Cu intake. However, data from observation studies should be regarded with caution because of uncertainties regarding Cu concentration in various foods and water. Further studies that accurately evaluate Cu exposure based on reliable biomarkers of Cu status are needed.
Zinc (Zn) and copper (Cu) are essential for optimal innate immune function and nutritional deficiency in either metal leads to increased susceptibility to bacterial infection. Recently, the decreased survival of bacterial pathogens with impaired Cu and/or Zn detoxification systems in phagocytes and animal models of infection has been reported. Consequently, a model has emerged in which the host utilises Cu and/or Zn intoxication to reduce the intracellular survival of pathogens within phagocytes. This review describes and assesses the potential role for Cu and Zn intoxication in innate immune function and their direct bactericidal function.
Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
Classification, chemistry, and applications of fullerenes, carbon dots, nanotubes, graphene, nanodiamonds, and combined superstructures of a range of carbon nanoallotropes are investigated. The investigations also cover superstructures consisting of combinations of carbon nanoallotropes such as fullerene aggregates, CNTs or graphene thin films, fibers, membranes, and aerogels in addition to describing individual carbon nanoallotropes. The issue of chemical modification of carbon nanoallotropes with division into several sections based on the origins of the chemical reactivity in each case is also investigated.
Biocompatible synthetic scaffolds with enhanced osteogenic and angiogenic capacity are of great interest for the repair of large (critical size) bone defects. In this study, we investigated an approach based on the controlled delivery of copper (Cu) ions from borate bioactive glass scaffolds for stimulating angiogenesis and osteogenesis in a rodent calvarial defect model. Borate glass scaffolds (pore size = 200–400 μm) doped with varying amounts of Cu (0–3.0 wt% CuO) were created using a polymer foam replication technique. When immersed in simulated body fluid (SBF) in vitro, the scaffolds released Cu ions into the medium at a rate that was dependent on the amount of Cu in the glass and simultaneously converted to hydroxyapatite (HA). At the concentrations used, the Cu in the glass was not cytotoxic to human bone marrow derived stem cells (hBMSCs) cultured on the scaffolds and the alkaline phosphatase activity of the hBMSCs increased with increasing Cu in the glass. When implanted in rat calvarial defects for 8 weeks, the scaffolds doped with 3 wt% CuO showed a significantly better capacity to stimulate angiogenesis and regenerate bone when compared to the undoped glass scaffolds. Together, these results indicate that the controlled delivery of Cu ions from borate bioactive glass implants is a promising approach in healing bone defects.
Copper (Cu) is an essential microelement found in all living organisms with the unique ability to adopt two different redox states-in the oxidized (Cu(2+)) and reduced (Cu(+)). It is required for survival and serves as an important catalytic cofactor in redox chemistry for proteins that carry out fundamental biological functions, important in growth and development. The deficit of copper can result in impaired energy production, abnormal glucose and cholesterol metabolism, increased oxidative damage, increased tissue iron (Fe) accrual, altered structure and function of circulating blood and immune cells, abnormal neuropeptides synthesis and processing, aberrant cardiac electrophysiology, impaired myocardial contractility, and persistent effects on the neurobehavioral and the immune system. Increased copper level has been found in several disorders like e.g.: Wilson's disease or Menke's disease. New findings with the great potential for impact in medicine include the use of copper-lowering therapy for antiangiogenesis, antifibrotic and anti-inflammatory purposes. The role of copper in formation of amyloid plaques in Alzheimer's disease, and successful treatment of this disorder in rodent model by copper chelating are also of interest. In this work we will try to describe essential aspects of copper in chosen diseases. We will represent the evidence available on adverse effect derived from copper deficiency and copper excess. We will try to review also the copper biomarkers (chosen enzymes) that help reflect the level of copper in the body.
Regulatory T (Treg) cells constitute a distinct T cell subset, which plays a key role in immune tolerance and homeostasis. The transcription factor Foxp3 controls a substantial part of Treg cell development and function. Yet its expression alone is insufficient for conferring developmental and functional characteristics of Treg cells. There is accumulating evidence that concurrent induction of Treg-specific epigenetic changes and Foxp3 expression is crucial for lineage specification and functional stability of Treg cells. This review discusses recent progress in our understanding of molecular features of Treg cells, in particular, the molecular basis of how a population of developing T cells is driven to the Treg cell lineage and how its function is stably maintained.
Hydrogels are used as scaffolds for tissue engineering, vehicles for drug delivery, actuators for optics and fluidics, and model extracellular matrices for biological studies. The scope of hydrogel applications, however, is often severely limited by their mechanical behaviour. Most hydrogels do not exhibit high stretchability; for example, an alginate hydrogel ruptures when stretched to about 1.2 times its original length. Some synthetic elastic hydrogels have achieved stretches in the range 10-20, but these values are markedly reduced in samples containing notches. Most hydrogels are brittle, with fracture energies of about 10 J m(-2) (ref. 8), as compared with ∼1,000 J m(-2) for cartilage and ∼10,000 J m(-2) for natural rubbers. Intense efforts are devoted to synthesizing hydrogels with improved mechanical properties; certain synthetic gels have reached fracture energies of 100-1,000 J m(-2) (refs 11, 14, 17). Here we report the synthesis of hydrogels from polymers forming ionically and covalently crosslinked networks. Although such gels contain ∼90% water, they can be stretched beyond 20 times their initial length, and have fracture energies of ∼9,000 J m(-2). Even for samples containing notches, a stretch of 17 is demonstrated. We attribute the gels' toughness to the synergy of two mechanisms: crack bridging by the network of covalent crosslinks, and hysteresis by unzipping the network of ionic crosslinks. Furthermore, the network of covalent crosslinks preserves the memory of the initial state, so that much of the large deformation is removed on unloading. The unzipped ionic crosslinks cause internal damage, which heals by re-zipping. These gels may serve as model systems to explore mechanisms of deformation and energy dissipation, and expand the scope of hydrogel applications.
Bacterial infection and excess reactive oxygen species are key factors that lead to slow or substantially delayed wound healing. It is crucial to design and develop new nanomaterials with antibacterial and antioxidative capabilities for wound healing. Here, positively charged carbon dots (CDs) are rationally designed and synthesized from p-phenylenediamine and polyethyleneimine by a facile one-pot solvothermal method, which show good biocompatibility in in vitro cytotoxicity, hemolysis assays, and in vivo toxicity evaluation. The positively charged CDs show superior antimicrobial effect against Staphylococcus aureus (S. aureus) at very low concentrations, reducing the risk of wound infection. At the same time, CDs with surface defects and unpaired electrons can effectively scavenge excess free radicals to reduce oxidative stress damage, accelerate wound inflammation-proliferation transition, and promote wound healing. The mouse model of skin infection demonstrates that CDs can effectively promote the wound healing of skin infection without obvious side effects by simply dropping or spraying onto the wound. We believe that the prepared CDs have satisfactory biocompatibility, antioxidant capacity, and excellent antibacterial activity and have great application potential in wound healing.
The bone remodeling process is crucial for titanium (Ti) osseointegration and involves the crosstalk between osteoclasts and osteoblasts. Considering the high osteogenic potential of Ti with nanotopography (Ti Nano) and that osteoclasts inhibit osteoblast differentiation, we hypothesized that nanotopography attenuate the osteoclast-induced disruption of osteoblast differentiation. Osteoblasts were co-cultured with osteoclasts on Ti Nano and Ti Control and non-co-cultured osteoblasts were used as control. Gene expression analysis using RNAseq showed that osteoclasts downregulated the expression of osteoblast marker genes and upregulated genes related to histone modification and chromatin organization in osteoblasts grown on both Ti surfaces. Osteoclasts also inhibited the mRNA and protein expression of osteoblast markers, and such effect was attenuated by Ti Nano. Also, osteoclasts increased the protein expression of H3K9me2, H3K27me3 and EZH2 in osteoblasts grown on both Ti surfaces. ChIP assay revealed that osteoclasts increased accumulation of H3K27me3 that represses the promoter regions of Runx2 and Alpl in osteoblasts grown on Ti Control, which was reduced by Ti Nano. In conclusion, these data show that despite osteoclast inhibition of osteoblasts grown on both Ti Control and Ti Nano, the nanotopography attenuates the osteoclast-induced disruption of osteoblast differentiation by preventing the increase of H3K27me3 accumulation that represses the promoter regions of some key osteoblast marker genes. These findings highlight the epigenetic mechanisms triggered by nanotopography to protect osteoblasts from the deleterious effects of osteoclasts, which modulate the process of bone remodeling and may benefit the osseointegration of Ti implants.
3D printing is known as a cost-effective technique that shows huge potential in fabrication of graft substitutes for bone tissue regeneration. However, the tradeoff between 3D printability, mechanical strength and bioactivity of the printed materials (i.e., inks) remains a challenge. In this work, we present a novel photocrosslinkable nanocomposite ink composed of tri-block poly (lactide-co-propylene glycol-co-lactide) dimethacrylate (PmLnDMA, m and n respectively represent the unit length of propylene glycol and lactide) and hydroxyethyl methacrylate (HEMA)-functionalized hydroxyapatite nanoparticles (nHAMA). The reactive HEMA-conjugated nHAMA, is designed to covalently crosslink with the surrounding polymer matrix to further increase the interfacial bonding between them. We find that the nHAMA can rapidly interact with PmLnDMA upon light exposure within 140 s and form an inorganic-organic co-crosslinked nanocomposite network, further enhancing the nanofiller-matrix interfacial compatibility. Notably, our nanocomposites possess significantly improved mechanical performances compared to the polymer, with compressive modulus increasing by nearly 10 times (from ⁓40 to ⁓400 MPa). Moreover, thanks to the low exothermic heat generation (<37 °C) during photocrosslinking, our nanocomposite ink enables facile encapsulation and long-term release of heat-labile biomolecules like bone morphogenic protein-2 (BMP-2). Furthermore, it demonstrates a readily tunable rheological property, wettability, degradation, and printability as a 3D bone scaffold. Together with its superior osteogenic ability both in vitro and in vivo, we envision that our nanocomposite ink holds great promise in 3D printing of bone grafts.
Hydroxyapatite (HA), the traditional bone tissue replacement material was widely used in the clinical treatment of bone defects because of its excellent biocompatibility. However, the processing difficulty and poor osteoinductive ability greatly limit the application of HA. Although many strategies have been reported to improve the machinability and osteointegration ability, the performance including mechanical strength, porosity, cell adhesion, etc. of material still can not meet the requirements. In this work, a soft template method was developed and a porous scaffold with hierarchical pore structure, nano surface morphology, suitable porosity and pore size, and good biomechanical strength was successfully prepared. The hierarchical pore structure is beneficial for cell adhesion, fluid transfer, and cell ingrowth. Moreover, the loaded reduced graphene oxide (rGO) can improve the adhesion and promote the proliferation and spontaneous osteogenic differentiation bone marrow mesenchymal stem cells. The scaffold is then crushed, degraded and wrapped by the newly-formed bone and the newly-formed bone gradually replaces the scaffold. The degradation rate of the scaffold well matches the rate of the new bone formation. The hierarchical porous HA/rGO composite scaffolds can greatly accelerate the bone ingrowth in the scaffold and bone repair in critical bone defects, thus providing a clinical potential candidate for large segment bone tissue engineering.
The host immune response to bone biomaterials is vital in determining scaffold fates and bone regeneration outcomes. The nanometer-scale interface of biomaterials, which independently controls physical inputs to cells, regulates osteogenic differentiation of stem cells and local immune response. Herein, we fabricated biomimetic hierarchical intrafibrillarly mineralized collagen (HIMC) with a bone-like staggered nanointerface and investigated its immunomodulatory properties and mesenchymal stem cell (MSC) recruitment during endogenous bone regeneration. The acquired HIMC potently induced neo-bone formation by promoting CD68+CD163+ M2 macrophage polarization and CD146+STRO-1+ host MSC recruitment in critical-sized bone defects. Mechanistically, HIMC facilitated M2 macrophage polarization and interleukin (IL)-4 secretion to promote MSC osteogenic differentiation. An anti-IL4 neutralizing antibody significantly reduced M2 macrophage-mediated osteogenic differentiation of MSCs. Moreover, HIMC-loaded-IL-4 implantation into critical-sized mandible defects dramatically enhanced bone regeneration and CD68+CD163+ M2 macrophage polarization. The depletion of monocyte/macrophages by clodronate liposomes significantly impaired bone regeneration by HIMC, but did not affect MSC recruitment. Thus, in emulating natural design, the hierarchical nanointerface possesses the capacity to recruit host MSCs and promote endogenous bone regeneration by immunomodulation of macrophage polarization through IL-4.
The development, maintenance of healthy bone and regeneration of injured tissue in the human body comprise a set of intricate and finely coordinated processes. However, an analysis of current bone regeneration strategies shows that only a small fraction of well-reported bone biology aspects has been used as inspiration and transposed into the development of therapeutic products. Specific topics that include inter-scale bone structural organization, developmental aspects of bone morphogenesis, bone repair mechanisms, role of specific cells and heterotypic cell contact in the bone niche (including vascularization networks and immune system cells), cell-cell direct and soluble-mediated contact, extracellular matrix composition (with particular focus on the non-soluble fraction of proteins), as well as mechanical aspects of native bone will be the main reviewed topics. In this Review we suggest a systematic parallelization of (i) fundamental well-established biology of bone, (ii) updated and recent advances on the understanding of biological phenomena occurring in native and injured tissue, and (iii) critical discussion of how those individual aspects have been translated into tissue regeneration strategies using biomaterials and other tissue engineering approaches. We aim at presenting a perspective on unexplored aspects of bone physiology and how they could be translated into innovative regeneration-driven concepts.
Novel strategies utilizing magnetic nanoparticles (MNPs) and magnetic fields are being developed to enhance bone tissue engineering efficacy. This article first reviewed cutting-edge research on the osteogenic enhancements via magnetic fields and MNPs. Then the current developments in magnetic strategies to improve the cells, scaffolds and growth factor deliveries were described. The magnetic-cell strategies included cell labeling, targeting, patterning, and gene modifications. MNPs were incorporated to fabricate magnetic composite scaffolds, as well as to construct delivery systems for growth factors, drugs and gene transfections. The novel methods using magnetic nanoparticles and scaffolds with magnetic fields and stem cells increased the osteogenic differentiation, angiogenesis and bone regeneration by 2-3 folds over those of the controls. The mechanisms of magnetic nanoparticles and scaffolds with magnetic fields and stem cells to enhance bone regeneration were identified as involving the activation of signaling pathways including MAPK, integrin, BMP and NF-κB. Potential clinical applications of magnetic nanoparticles and scaffolds with magnetic fields and stem cells include dental, craniofacial and orthopedic treatments with substantially increased bone repair and regeneration efficacy.
Bone osteogenesis is a complex phenomenon dependent on numerous microenvionmental cues, with their synchrony regulating cellular functions such as mechanical signaling, survival, proliferation and differentiation, as well as controlled regional specification of skeletal progenitor cell fate. Therefore, obtaining a mechanistic understanding of cellular response to a micro-environment is now coming into intense focus, which will facilitate the design of programmable biomaterials for regenerative medicine. State-of-the-art nano-material synthesis and self-assembly processes yield complex structures that mimic surface properties, composition and partially the morphology of the extracellular matrix. However, determining key structural properties that control cell attachment has been challenging, and contradictory results are reported regarding the mechanisms and roll of nanostructured materials. Here, we significantly improve osteogenesis on bio-inert substrates, demonstrating an exemplary organic-inorganic interface for superior prosthesis biointegration. We identify critical micro-scale hierarchical features that drastically enhance the cellular response to the same nano-scale architecture. It was observed that hierarchical morphologies, with a porosity above 80%, promote early-stage osteo-induction as indicated by extensive coating in-growth and nano-filopodia formation. We determined that cellular integration was mediated by two-way recognition of specific nano- and micro-topographical cues between the host tissue and cellular micro-environment. This has allowed us to detail a set of determinant features for the nanofabrication of advanced prosthesis coatings that may ultimately improve implant longevity.
Statement of significance:
Biphasic Calcium Phosphates (BCP) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalium Phosphate (β-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surgery. Doping can advantageously be used to improve their biological behaviors; however, it is important to describe the doping mechanism of BCP thoroughly in order to fully appraise the benefit of the doping process. The present paper scrutinizes in detail the incorporation of copper cation in order to correctly interpret the behavior of the Cu-doped bioceramic in biological fluid. The understanding of the copper doping mechanism, related to doping mechanism of others 3d-metal cations, makes it possible to explain the rates and kinetic of release of the dopant in biological medium. Finally, the knowledge of the behavior of the copper doped ceramic in biological environment allowed the tuning of its cytotoxicity properties. The present study resulted on pre-treated ceramic disks which have been evaluated as promising biocompatible ceramic for bone substitute and/or prosthesis coating: good adherence of bone marrow cells with good cell viability.
In recent years the potential application of nanocomposite biomaterials in tissue engineering field is gaining importance because of the combined features of all the individual components. A bottom-up approach is acquired in this study to recreate the bone microenvironment. The regenerated silk protein fibroin obtained from nonmulberry tropical tasar Antheraea mylitta species is reinforced with functionalized carbon nano fiber (CNF) and the composite sponges are fabricated using facile green aqueous based method. Biophysical investigations show that the matrices are porous and simultaneously bioactive when incubated in simulated body fluid. The reinforcement of CNF influences the mechanical property of the matrices by increasing the compressive modulus up to 46.54 MPa (∼4.3 times of the control fibroin sponge) in hydrated state, which is higher than the minimum required human trabecular bone modulus (10 MPa). The composite matrices are found to be non-hemolytic as well as cytocompatible. The growth factors (BMP-2 and TGF-β1) loaded composites show sustained release kinetics and an early attachment, growth, proliferation, and osteogenic differentiation of the osteoblasts and mesenchymal stem cells. The matrices are immunocompatible as evidenced by minimal release of pro-inflammatory cytokines both in vitro and in vivo. In order to support the in vitro study, in vivo analysis of new bone formation within the implants is performed through radiological, μ-CT, fluorochrome labeling and histological analysis, which show statistically better bone formation on growth factor loaded composite scaffolds. The study clearly shows the potential attributes of these composite matrices as an extra cellular matrix for supporting successful osseointegration process.
It is an ambitious target to improve overall Hepatocellular carcinoma therapeutic effects. Recently, MW ablation has emerged as a powerful thermal ablation technique, affording favorable survival with excellent local tumor control. To achieve better therapeutic effects of MW ablation, MW sensitizers are prepared for enhanced MW ablation to preferentially heat tumor territory. However, it is still not practicable for treatment of the orthotopic transplantation tumor. Herein, biocompatible and degradable mPEG-PLGA microcapsules with hierarchical structure have been designed for microwave-induced tumor therapy. Chemical drug doxorubicin hydrochloride (DOX·HCl), microwave (MW) sensitizers and CT imaging contrast MoS2 nanosheets and MR imaging contrast Fe3O4 nanoparticles are co-incorporated into the microcapsules. In vitro/vivo MR/CT dualmodal imaging results prove the potential application for guiding synergetic therapy and predicting post-therapy tumor progression in the orthotopic transplantation tumor model. After blocking the tumor-feeding arteries, these microcapsules not only exclude the cooling effect by cutting off the blood flow but also enhance MW heating conversion at tumor site. The focused MW heating makes microcapsules mollescent or ruptured and releases DOX·HCl from the microcapsules, achieving the controlled release of drugs for chemical therapy. Compared with MW ablation, 29.4% increase of necrosis diameter of normal liver in rabbit is obtained under MW ablation combined with transcatheter arterial blocking, and the average size of necrosis and inhibition rate of VX-2 liver tumor in rabbit has increased by 129.33% and 73.46%. Moreover, it is proved that the superselectively arterial administration of the as-prepared microcapsules has no recognizable toxicity on the animals. Therefore, this research provides a novel strategy for the construction of MW-induced microcapsules for orthotopic transplantation tumor ablation with the properties of MW sensitizing, superselective arterial blocking, control release and enhanced accumulation of DOX·HCl, and MR/CT dualmodal imaging, which exhibit great potential applications in the field of HCC therapy.
Bone diseases/injuries have been driving an urgent quest for bone substitutes for bone regeneration. Nanoscaled materials with bone-mimicking characteristics may create suitable microenvironments to guide effective bone regeneration. In this review, the natural hierarchical architecture of bone and its regeneration mechanisms are elucidated. Recent progress in the development of nanomaterials which can promote bone regeneration through bone-healing mimicry (e.g., compositional, nanocrystal formation, structural, and growth factor-related mimicking) is summarized. The nanoeffects of nanomaterials on the regulation of bone-related biological functions are highlighted. How to prepare nanomaterials with combinative bone-biomimicry features according to the bone healing process is prospected in order to achieve rapid bone regeneration in situ.
A ternary composite of graphene oxide/carbon dots/polypyrrole (GO/CDs/PPy) used as electrode active material for supercapacitor has been synthesized via in situ polymerization of GO/CDs with pyrrole under a mild condition. The CDs sandwiched between GO film and PPy layer can promote electron transportation in the ternary composite and thus reduce the internal resistance and charge transfer resistance of the electrode. Additionally, the CDs with large specific surface area can enhance the interfacial property among GO, CDs and PPy and increase the dielectric constant of the ternary composite. Notably, GO/CDs/PPy exhibits a specific capacitance of 576 F g⁻¹ at a current density of 0.5 A g⁻¹, and a supercapacitor fabricated by two symmetric GO/CDs/PPy electrodes owns a high energy density of 30.1 Wh kg⁻¹ at a power density of 250 W kg⁻¹. More importantly, the as–fabricated supercapacitor can keep an excellent cycle stability after 5000 cycles. In practice, a simple device assembled by five supercapacitors in series could power 59 light–emitting diode indicators for more than 60 s after only charging for 17 s. This work demonstrates that CDs can play an important and unique role in improving performance of a hybrid electric double layer capacitor (EDLC)/pseudocapacitor.
The development of hybrid biomaterials has been attracting great attention in the design of materials for biomedicine. The nanosized level of inorganic and organic or even bioactive components can be combined into a single material by this approach, which has created entirely new advanced compositions with truly unique properties for drug delivery. The recent advances in using hybrid nanovehicles as remotely controlled therapeutic delivery carriers are summarized with respect to different nanostructures, including hybrid host-guest nanoconjugates, micelles, nanogels, core-shell nanoparticles, liposomes, mesoporous silica, and hollow nanoconstructions. In addition, the controlled release of guest molecules from these hybrid nanovehicles in response to various remote stimuli such as alternating magnetic field, near infrared, or ultrasound triggers is further summarized to introduce the different mechanisms of remotely triggered release behavior. Through proper chemical functionalization, the hybrid nanovehicle system can be further endowed with many new properties toward specific biomedical applications.
The interest in nanotechnology and the growing concern for the antibiotic resistance demonstrated by many microorganisms have recently stimulated many efforts in designing innovative biomaterials and substrates with antibacterial properties. Among the implemented strategies to control the incidence of infections associated to the use of biomedical device and implants, interesting routes are represented by the incorporation of bactericidal agents onto the surface of biomaterials for the prevention of bacterial adhesion and biofilm growth. Natural products and particularly bioactive metals such as silver, copper and zinc represent an interesting alternative for the development of advanced biomaterials with antimicrobial properties. This review presents an overview of recent progress in the modification of biomaterials as well as the most attractive techniques for the deposition of antimicrobial coatings on different substrates for biomedical application. Moreover, some research activities and results achieved by the authors in the development of antibacterial materials are also presented and discussed.
Inspired by nature's toughening mechanisms, we designed a new polyhedral oligomeric silsesquioxane (POSS)-derived hybrid glass (PHG) that has covalent interactions on the molecular scale between the inorganic POSS cage and organic phase. These features allow "elastic deformation" of the inorganic POSS cage in limited scale. The final product is a bulk hybrid material with toughness (3.56 ± 0.25 MPa·m(1/2)) similar to natural bone (2.4-5.3 MPa·m(1/2)). PHG exhibited excellent bioactivity by promoting the formation of plate-like hydroxyapatite on its surface in simulated body fluid and showed good cell adhesion. PHG also can be a platform to guide adipose tissue-derived mesenchymal stem cells differentiation and mineralization. The key structural features of this material can be used to guide the design of bio-inspired composites with unique toughness, which would be of great benefit to hard tissue engineering.
Copyright © 2015 Elsevier Ltd. All rights reserved.
The aim of our study was to investigate the osteoinductive potential of a titanium (Ti) surface with nanotopography, using mesenchymal stem cells (MSCs) and the mechanism involved in this phenomenon. Polished Ti discs were chemically treated with H2 SO4 /H2 O2 to yield nanotopography and rat MSCs were cultured under osteogenic and non-osteogenic conditions on both nanotopography and untreated polished (control) Ti surfaces. The nanotopography increased cell proliferation and alkaline phosphatase (Alp) activity and upregulated the gene expression of key bone markers of cells grown under both osteogenic and non-osteogenic conditions. Additionally, the gene expression of α1 and β1 integrins was higher in cells grown on Ti with nanotopography under non-osteogeneic condition compared with control Ti surface. The higher gene expression of bone markers and Alp activity induced by Ti with nanotopography was reduced by obtustatin, an α1β1 integrin inhibitor. These results indicate that α1β1 integrin signaling pathway determines the osteoinductive effect of nanotopography on MSCs. This finding highlights a novel mechanism involved in nanosurface-mediated MSCs fate and may contribute to the development of new surface modifications aiming to accelerate and/or enhance the process of osseointegration. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
Bone healing commences with an inflammatory reaction which initiates the regenerative healing process leading in the end to reconstitution of bone. An unbalanced immune reaction during this early bone healing phase is hypothesized to disturb the healing cascade in a way that delays bone healing and jeopardizes the successful healing outcome. The immune cell composition and expression pattern of angiogenic factors were investigated in a sheep bone osteotomy model and compared to a mechanically-induced impaired/delayed bone healing group. In the impaired/delayed healing group, significantly higher T cell percentages were present in the bone hematoma and the bone marrow adjacent to the osteotomy gap when compared to the normal healing group. This was mirrored in the higher cytotoxic T cell percentage detected under delayed bone healing conditions indicating longer pro-inflammatory processes. The highly activated periosteum adjourning the osteotomy gap showed lower expression of hematopoietic stem cell markers and angiogenic factors such as heme oxygenase and vascular endothelial growth factor. This indicates a deferred revascularization of the injured area due to ongoing pro-inflammatory processes in the delayed healing group. Results from this study suggest that there are unfavorable immune cells and factors participating in the initial healing phase. In conclusion, identifying beneficial aspects may lead to promising therapeutical approaches that might benefit further by eliminating the unfavorable factors.
Current trends in clinical dental implant therapy include use of endosseous dental implant surfaces embellished with nanoscale topographies. The goal of this review is to consider the role of nanoscale topographic modification of titanium substrates for the purpose of improving osseointegration. Nanotechnology offers engineers and biologists new ways of interacting with relevant biological processes. Moreover, nanotechnology has provided means of understanding and achieving cell specific functions. The various techniques that can impart nanoscale topographic features to titanium endosseous implants are described. Existing data supporting the role of nanotopography suggest that critical steps in osseointegration can be modulated by nanoscale modification of the implant surface. Important distinctions between nanoscale and micron-scale modification of the implant surface are presently considered. The advantages and disadvantages of nanoscale modification of the dental implant surface are discussed. Finally, available data concerning the current dental implant surfaces that utilize nanotopography in clinical dentistry are described. Nanoscale modification of titanium endosseous implant surfaces can alter cellular and tissue responses that may benefit osseointegration and dental implant therapy.