A comprehensive understanding of the key microenvironmental signals regulating bone regeneration is pivotal for the effective design of bioinspired orthopedic materials. Here, we identified citrate ...as an osteopromotive factor and revealed its metabonegenic role in mediating citrate metabolism and its downstream effects on the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Our studies show that extracellular citrate uptake through solute carrier family 13, member 5 (SLC13a5) supports osteogenic differentiation via regulation of energy-producing metabolic pathways, leading to elevated cell energy status that fuels the high metabolic demands of hMSC osteodifferentiation. We next identified citrate and phosphoserine (PSer) as a synergistic pair in polymeric design, exhibiting concerted action not only in metabonegenic potential for orthopedic regeneration but also in facile reactivity in a fluorescent system for materials tracking and imaging. We designed a citrate/phosphoserine-based photoluminescent biodegradable polymer (BPLP-PSer), which was fabricated into BPLP-PSer/hydroxyapatite composite microparticulate scaffolds that demonstrated significant improvements in bone regeneration and tissue response in rat femoral-condyle and cranial-defect models. We believe that the present study may inspire the development of new generations of biomimetic biomaterials that better recapitulate the metabolic microenvironments of stem cells to meet the dynamic needs of cellular growth, differentiation, and maturation for use in tissue engineering.
The impact of metabolic regulation is receiving increasing appreciation in regeneration engineering scenarios. An overview of how regulation of cell metabolism contributes to modulation of cell ...function is presented, together with a summary of recent evidence supporting the notion that materials could be engineered to regulate cell metabolism for improved regeneration outcome.
Recent advances in cell metabolism studies have deepened the appreciation of the role of metabolic regulation in influencing cell behavior during differentiation, angiogenesis, and immune response in the regenerative engineering scenarios. However, the understanding of whether the intracellular metabolic pathways could be influenced by material‐derived cues remains limited, although it is now well appreciated that material cues modulate cell functions. Here, an overview of how the regulation of different aspect of cell metabolism, including energy homeostasis, oxygen homeostasis, and redox homeostasis could contribute to modulation of cell function is provided. Furthermore, recent evidence demonstrating how material cues, including the release of inherent metabolic factors (e.g., ions, regulatory metabolites, and oxygen), tuning of the biochemical cues (e.g., inherent antioxidant properties, cell adhesivity, and chemical composition of nanomaterials), and changing in biophysical cues (topography and surface stiffness), may impact cell metabolism toward modulated cell behavior are discussed. Based on the resurgence of interest in cell metabolism and metabolic regulation, further development of biomaterials enabling metabolic regulation toward dictating cell function is poised to have substantial implications for regenerative engineering.
Biomaterial mediated bone regeneration is an attractive strategy for bone defect treatment. Organic/inorganic composites have been well established as effective bone graft. Here, the bone ...regenerative effect of the composites made from tannic acid (TA) modified hydroxyapatite (HA) (THA) or TA & silver nanoparticles (Ag NPs) modified HA (Ag-THA) and polyurethane (PU) was evaluated on critical-sized calvarial defects in rats. The in vivo study indicates that PU/THA and PU/Ag-THA scaffolds exhibited acceptable biocompatibility and induced significantly enhanced bone mineral densities comparing with the blank control (CON) group as well as PU/HA group. The inclusion of TA on HA brought the composites with enhanced osteogenesis and angiogenesis, evidenced by osteocalcin (OCN) and vascular endothelial growth factor (VEGF) immunohistochemical staining. Tartrate resistant acid phosphatase (TRAP) staining showed high osteoclast activity along with osteogenesis, especially in PU/THA and PU/Ag-THA groups. However, further introduction of Ag NPs on HA depressed the angiogenesis of the composites, leading to even lower VEGF expression than that of CON group. This study once more proved that THA can serve as a better bone composite component that pure HA and can promote osteogenesis and angiogenesis. While, the introduction of antimicrobial Ag NPs on HA need to be controlled in some extent not to affect the angiogenesis of the composites.
Citrate based polymer poly(octamethylene citrate) (POC) has shown promise when formulated into composite material containing up to 65 wt% hydroxylapatite (HA) for orthopedic applications. Despite ...significant research into POC, insufficient information about the biocompatibility of the monomers 1,8-Octanediol and Citrate used in its synthesis is available. Herein, we investigated the acute cytotoxicity, immune response, and long-term functionality of both monomers. Our results showed a cell-type dependent cytotoxicity of the two monomers: 1,8-Octanediol induced less acute toxicity to 3T3 fibroblasts than Citrate while presenting comparable cytotoxicity to MG63 osteoblast-like cells; however, Citrate demonstrated enhanced compatibility with hMSCs compared to 1,8-Octanediol. The critical cytotoxic concentration values EC30 and EC50, standard for comparing cytotoxicity of chemicals, were also provided. Additionally, Citrate showed slower and less inhibitory effects on long-term hMSC cell proliferation compared with 1,8-Octanediol. Furthermore, osteogenic differentiation of hMSCs exposure to Citrate resulted in less inhibitory effect on alkaline phosphatase (ALP) production. Neither monomer triggered undesired pro-inflammatory responses. In combination with diffusion model analysis of monomer release from cylindrical implants, based on which the maximum concentration of monomers in contact with bone tissue was estimated to be 2.2 × 10−4 mmol/L, far lower than the critical cytotoxic concentrations as well as the 1,8-Octanediol concentration (0.4 mg/mL or 2.7 mmol/L) affecting hMSCs differentiation, we provide strong evidence for the cytocompatibility of the two monomers degraded from citrate-based composites in the orthopedic setting.
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•It was the first time to comprehensively evaluate the cytotoxicity of 1,8-Octanediol and Citrate.•The effect of 1,8-Octanediol and Citrate on osteogenic differentiation was investigated.•A diffusion model was established to estimate the in vivo monomer release and diffusion.
Leveraging the multifunctional nature of citrate in chemistry and inspired by its important role in biological tissues, a class of highly versatile and functional citrate-based materials (CBBs) has ...been developed via facile and cost-effective polycondensation. CBBs exhibiting tunable mechanical properties and degradation rates, together with excellent biocompatibility and processability, have been successfully applied in vitro and in vivo for applications ranging from soft to hard tissue regeneration, as well as for nanomedicine designs. We summarize in the review, chemistry considerations for CBBs design to tune polymer properties and to introduce functionality with a focus on the most recent advances, biological functions of citrate in native tissues with the new notion of degradation products as cell modulator highlighted, and the applications of CBBs in wound healing, nanomedicine, orthopedic, cardiovascular, nerve and bladder tissue engineering. Given the expansive evidence for citrate's potential in biology and biomaterial science outlined in this review, it is expected that citrate based materials will continue to play an important role in regenerative engineering.
An increasing number of patients are being diagnosed with neurological diseases, but are rarely cured because of the lack of curative therapeutic approaches. This situation creates an urgent clinical ...need to develop effective diagnosis and treatment strategies for repair and regeneration of injured or diseased neural tissues. In this regard, biodegradable functional biomaterials provide promising solutions to meet this demand owing to their unique responsiveness to external stimulation fields, which enable neuro-imaging, neuro-sensing, specific targeting, hyperthermia treatment, controlled drug delivery, and nerve regeneration. This review discusses recent progress in the research and development of biodegradable functional biomaterials including electroactive biomaterials, magnetic materials and photoactive biomaterials for the management of neurological disorders with emphasis on their applications in bioimaging (photoacoustic imaging, MRI and fluorescence imaging), biosensing (electrochemical sensing, magnetic sensing and opical sensing), and therapy strategies (drug delivery, hyperthermia treatment, and tissue engineering). It is expected that this review will provide an insightful discussion on the roles of biodegradable functional biomaterials in the diagnosis and treatment of neurological diseases, and lead to innovations for the design and development of the next generation biodegradable functional biomaterials.
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Abstract Many kinds of cancer are difficult to treat because of their highly metastatic abilities. Thus, seeking new anticancer drugs or therapy strategies, which could reduce the motility of cancer ...cells or inhibit the migration and invasion of the cells, is an urgent affair. Several recent reports suggest various techniques (such as layer-by-layer assembly and biomimetic mineralization) aimed to functionalize human cells and microbial with polyelectrolytes, nanoparticles, or mineral coatings. Inspired by these studies, an artificial mineral shell could be formed to enclose cancer cells under the regulation of SIBLINGs-like proteins. Consequently, the connection between the cancer cell and substrate would be interfered or inhibited. Therefore, the motility of cancer cells would be weakened or inhibited due to the restriction of the artificial mineral shell. This hypothetical strategy might be as a new concept for cancer therapy.
To develop more biomarkers for diagnosis and therapy of ovarian cancer, a 12-mer phage display library was used to isolate peptides that bound specifically to the human ovarian tumor cell line ...SK-OV-3. After five rounds of in vitro screening, the recovery rate of phages showed a 69-fold increase over the first round of washings and a group of phage clones capable of binding to SK-OV-3 cells were obtained. A phage clone named Z1 with high affinity and specificity to SK-OV-3 cells was identified in vitro. More importantly, the synthetic biotin-labeled peptide, ZP1 (=SVSVGMKPSPRP), which corresponded to the sequence of the inserted fragment of Z1, demonstrated a high specificity to SK-OV-3 cells especially when compared to other cell lines (A2780 and 3T3). ZP1 might therefore be a biomarker for targeting drug delivery in ovarian cancer therapy.
Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of ...cell‐mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer‐specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti‐BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP‐PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP‐PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell–cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The “self‐powered” immune cell‐mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.
By taking advantage of the innate immune cell's ability to target tumor cells, a novel drug delivery system is developed by using THP‐1 cells as both nanoparticle‐carriers and navigators to achieve cancer‐specific drug delivery. The “self‐powered” immune cell‐mediated theranostic biodegradable photoluminescent poly (lactic acid) nanoparticle‐based drug delivery system represents a potentially significant advancement in targeted theranostic cancer nanotechnologies.
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The design and development of bioactive materials that are inherently conducive for osteointegration and bone regeneration with tunable mechanical properties and degradation remains a ...challenge. Herein, we report the development of a new class of citrate-based materials with glycerophosphate salts, β-glycerophosphate disodium (β-GP-Na) and glycerophosphate calcium (GP-Ca), incorporated through a simple and convenient one-pot condensation reaction, which might address the above challenge in the search of suitable orthopedic biomaterials. Tensile strength of the resultant poly (octamethylene citrate glycerophosphate), POC-βGP-Na and POC-GP-Ca, was as high as 28.2 ± 2.44 MPa and 22.76 ± 1.06 MPa, respectively. The initial modulus ranged from 5.28 ± 0.56 MPa to 256.44 ± 22.88 MPa. The mechanical properties and degradation rate of POC-GP could be controlled by varying the type of salts, and the feeding ratio of salts introduced. Particularly, POC-GP-Ca demonstrated better cytocompatibility and the corresponding composite POC-GP-Ca/hydroxyapatite (HA) also elicited improved osteogenic differentiation of human mesenchymal stem cells (hMSCs) in vitro, as compared to POC-βGP-Na/HA and POC/HA. The superior in-vivo performance of POC-GP-Ca/HA microparticle scaffolds in promoting bone regeneration over POC-βGP-Na/HA and POC/HA was further confirmed in a rabbit femoral condyle defect model. Taken together, the tunability of mechanical properties and degradation rates, together with the osteopromotive nature of POC-GP polymers make these materials, especially POC-GP-Ca well suited for bone tissue engineering applications.
The design and development of bioactive materials that are inherently conducive for osteointegration and bone regeneration with tunable mechanical properties and degradation remains a challenge. Herein, we report the development of a new class of citrate-based materials with glycerophosphate salts, β-glycerophosphate disodium (β-GPNa) and glycerophosphate calcium (GPCa), incorporated through a simple and convenient one-pot condensation reaction. The resultant POC-GP polymers showed significantly improved mechanical property and tunable degradation rate. Within the formulation investigated, POC-GPCa/HA composite further demonstrated better bioactivity in favoring osteogenic differentiation of hMSCs in vitro and promoted bone regeneration in rabbit femoral condyle defects. The development of POC-GP expands the repertoire of the well-recognized citrate-based biomaterials to meet the ever-increasing needs for functional biomaterials in tissue engineering and other biomedical applications.
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