Biomimetic delivery of signals for bone tissue engineering

Bone tissue engineering is an exciting approach to directly repair bone defects or engineer bone tissue for transplantation.Biomaterials play a pivotal role in providing a template and extracellular environment to support regenerative cells and promote tissue regeneration. A variety of signaling cues have been identified to regulate cellular activity, tissue development, and the healing process. Numerous studies and trials have shown the promise of tissue engineering, but successful translations of bone tissue engineering research into clinical applications have been limited, due in part to a lack of optimal delivery systems for these signals. Biomedical engineers are therefore highly motivated to develop biomimetic drug delivery systems, which benefit from mimicking signaling molecule release or presentation by the native extracellular matrix during development or the natural healing process. Engineered biomimetic drug delivery systems aim to provide control over the location, timing, and release kinetics of the signal molecules according to the drug's physiochemical properties and specific biological mechanisms. This article reviews biomimetic strategies in signaling delivery for bone tissue engineering, with a focus on delivery systems rather than specific molecules. Both fundamental considerations and specific design strategies are discussed with examples of recent research progress, demonstrating the significance and potential of biomimetic delivery systems for bone tissue engineering.

Biomechanics and mechanobiology of the bone matrix

The bone matrix plays an indispensable role in the human body,and its unique biomechanical and mechanobiological properties have received much attention.The bone matrix has unique mechanical anisotropy and exhibits both strong toughness and high strength.These mechanical properties are closely associated with human life activities and correspond to the function of bone in the human body.None of the mechanical properties exhibited by the bone matrix is independent of its composition and structure.Studies on the biomechanics of the bone matrix can provide a reference for the preparation of more applicable bone substitute implants,bone biomimetic materials and scaffolds for bone tissue repair in humans,as well as for biomimetic applications in other fields.In providing mechanical support to the human body,bone is constantly exposed to mechanical stimuli.Through the study of the mechanobiology of the bone matrix,the response mechanism of the bone matrix to its surrounding mechanical environment can be elucidated and used for the health maintenance of bone tissue and defect regeneration.This paper summarizes the biomechanical properties of the bone matrix and their biological significance,discusses the compositional and structural basis by which the bone matrix is capable of exhibiting these mechanical properties,and studies the effects of mechanical stimuli,especially fluid shear stress,on the components of the bone matrix,cells and their interactions.The problems that occur with regard to the biomechanics and mechanobiology of the bone matrix and the corresponding challenges that may need to be faced in the future are also described.

Electrospinning of a sandwich-structured membrane with sustained release capability and long-term anti-inflammatory effects for dental pulp regeneration

Current electro spun membranes used for pulp capping still lack the sustained-release capability and long-term anti-inflammatory effects that are favorable for dental pulp regeneration.In this work,a single-layered poly(lac tic acid)(PLA)electro spun membrane loaded with amorphous calcium phosphate(ACP)and aspirin(PLA/ACP/Aspirin membrane,i.e.,PA A membrane)is sandwiched between two poly(lactic-co-glycolic acid)(PLGA)electro spun membranes as a novel sandwich-structured PLGA and PA A composite electro spun membrane(PLGA-PAA membrane)to resolve the need for sustained-release design and anti-inflammatory effects.Contact angle measurements indicate that the PLGA-PAA membrane is more hydrophilic than the PAA membrane.An in vitro release study reveals that PLGA membranes coated on PAA membrane could slightly slow down ion release,while signiificantly prolonging aspirin release.We also co-cultured membranes with dental pulp stem cells(DPSCs)and human monocytic THP-1 cells to evaluate their osteogenic ability and anti-inflammatory effects,respectively.Compared with the PAA membrane,the PLGA-PAA membrane promotes cell adhesion,proliferation,and osteogenic differentiation.A prolonged anti-inflammatory effect of up to 18 days is also observed in the PLGA-PAA group.The results suggest a promising strategy for fabricating an electro spun membrane system with controlled release capabilities and long-term anti-inflammatory effects for use as pulp-capping material for regeneration of the dentin-pulp complex.

Transformation Models for Survival Data Analysis with Applications

When the event of interest never occurs for a proportion of subjects during the study period, survival models with a cure fraction are more appropriate in analyzing this type of data. Considering the non-linear relationship between response variable and covariates, we propose a class of generalized transformation models motivated by Zeng et al. [1] transformed proportional time cure model, in which fractional polynomials are used instead of the simple linear combination of the covariates. Statistical properties of the proposed models are investigated, including identifiability of the parameters, asymptotic consistency, and asymptotic normality of the estimated regression coefficients. A simulation study is carried out to examine the performance of the power selection procedure. The generalized transformation cure rate models are applied to the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (NHANES1) for the purpose of examining the relationship between survival time of patients and several risk factors.

Collagen-based bioinks for regenerative medicine: Fabrication, application and prospective

In the field of regenerative medicine,the importance of 3D bioprinting is self-evident and nonnegligible.However,3D bioprinting technology also requires bioink with excellent performance as support material to fabricate a multi-functional bioinspired scaffold.Collagen-based bioink is regarded as an ideal 3D bioprinting ink for its excellent biocompatibility,controllable printability and cell loading property.It is an important breakthrough in regenerative medicine with the progress of collagen-based bioink,which fabricates bioinspired scaffolds with different functions and is applied in different repair scenarios.This review summarizes the different applications of collagen-based bioink and classifies them as soft tissue and hard tissue according to the target region.The applications of target region in soft tissues include skin,cartilage,heart and blood vessels,while in hard tissues include femur,skull,teeth and spine.When the collagen-based bioink is applied in repairing soft tissue,the requirements of function are higher,while the mechanical properties must be further improved in repairing hard tissue.We further summarize the characteristics of collagen-based bioink and point out the most important properties that should be considered in different repair scenarios,which can provide reference for the preparation of bioinks with different functions.Finally,we point out the main challenges faced by collagen-based bioink and prospect the future research directions.

MV-mediated biomineralization mechanisms and treatments of biomineralized diseases

As the quality of life improves,people pay more and more attention to health.They are concerned about the causes of diseases,and seek better treatments.The most common diseases are biomineralized diseases,four different kinds of typical examples among which are selected to elaborate their mechanisms and existing treatments.Whether it is tooth and bone in physiological mineralization or cartilage and blood vessel in pathological mineralization,they are all related to matrix vesicle(MV)-mediated biomineralization.MV-mediated biomineralization is the initial stage of biomineralization and the nucleation site mediating collagen mineralization.Definition,composition,biogenesis,and action mechanism of MVs are refined and expounded,especially a novel biomineralization pathway similar to exosome(EX)origin.Four differences are summarized to distinguish MVs and EXs.A series of treatments using MVs to solve biomineralized diseases such as tooth and bone defects,osteoarthritis and atherosclerosis are proposed,and the experimental extraction steps of MVs are summarized.

Composite double-layer microneedle loaded with traditional Chinese medicine for the treatment of androgenic alopecia

Androgenetic alopecia(AGA)is an androgen-mediated alopecia affected by both genes and hormones.Medication is a relatively common treatment.As a new drug delivery method,microneedles(MNs)can effectively break through the stratum corneum barrier,deliver drugs more efficiently,and achieve better therapeutic effects.In this study,we develop a composite double-layer MN through multi-step casting fabrication using a polydimethylsiloxane mold.The needle tip was fabricated by mixed solution of chitosan and polyvinylpyrrolidone which was loaded with Polygonum multiflorum extract,and the base layer was prepared by mixed solution of polyvinyl alcohol and polyvinylpyrrolidone.In vitro mechanical tests showed that the maximum load of a single tip of the drug-loaded MN was about 3.5 N,which met the mechanical requirements of skin puncture(>1 N).The drug release experiment showed that the MN could achieve gradual drug release.In the animal experiment,pigmentation and hair regrowth occurred earlier in the Polygonum multiflorum-MN(Pm-MN)group than in the other groups,and hair growth finally appeared in almost the entire area.Compared with the AGA model mice,mice in the Pm-MN group achieved an increase in the number and diameter of hair follicles.In conclusion,the Pm-MN is scientific and feasible for treating AGA.

Bioinspired mineralized collagen scaffolds for bone tissue engineering

Successful regeneration of large segmental bone defects remains a major challenge in clinical orthopedics,thus it is of important significance to fabricate a suitable alternative material to stimulate bone regeneration.Due to their excellent biocompatibility,sufficient mechanical strength,and similar structure and composition of natural bone,the mineralized collagen scaffolds(MCSs)have been increasingly used as bone substitutes via tissue engineering approaches.Herein,we thoroughly summarize the state of the art of MCSs as tissue-engineered scaffolds for acceleration of bone repair,including their fabrication methods,critical factors for osteogenesis regulation,current opportunities and challenges in the future.First,the current fabrication methods for MCSs,mainly including direct mineral composite,in-situ mineralization and 3D printing techniques,have been proposed to improve their biomimetic physical structures in this review.Meanwhile,three aspects of physical(mechanics and morphology),biological(cells and growth factors)and chemical(composition and cross-linking)cues are described as the critical factors for regulating the osteogenic feature of MCSs.Finally,the opportunities and challenges associated with MCSs as bone tissue-engineered scaffolds are also discussed to point out the future directions for building the next generation of MCSs that should be endowed with satisfactorily mimetic structures and appropriately biological characters for bone regeneration.

In vitro immunomodulation of magnesium on monocytic cell toward anti-inflammatory macrophages

Biodegradable magnesium(Mg)has shown great potential advantages over current bone fixation devices and vascular scaffold technologies;however,there are few reports on the immunomodulation of corrosive Mg products,the micron-sized Mg particles(MgMPs).Human monocytic leukemia cell line THP-1 was set as the in vitro cell model to estimate the immunomodulation of MgMPs on cell proliferation,apoptosis,polarization and inflammatory reaction.Our results indicated highconcentration of Mg^2+ demoted the proliferation of the THP-1 cells and,especially,THP-1-derived macrophages,which was a potential factor that could affect cell function,but meanwhile,cell apoptosis was almost not affected by Mg^2+.In particular,the inflammation regulatory effects of MgMPs were investigated.Macrophages exposed to Mg^2+ exhibited down-regulated expressions of M1 subtype markers and secretions of pro-inflammatory cytokines,up-regulated expression of M2 subtype marker and secretion of anti-inflammatory cytokine.These results indicated Mg^2+ could convert macrophages from M0 to M2 phenotype,and the bioeffects of MgMPs on human inflammatory cells were most likely due to the Mg^2+-induced NF-jB activation reduction.Together,our results proved Mg^2+ could be used as a new anti-inflammatory agent to suppress inflammation in clinical applications,which may provide new ideas for studying the immunomodulation of Mg-based implants on human immune system.