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Recent advances in additive manufacturing (AM) have enabled the fabrication of functionally graded porous biomaterials (FGPBs) for application as orthopedic implants and bone ...substitutes. Here, we present a step-wise topological design of FGPB based on diamond unit cells to mimic the structure of the femoral diaphysis. The FGPB was manufactured from Ti-6Al-4V powder using the selective laser melting (SLM) technique. The morphological parameters, permeability and mechanical properties of FGPB samples were measured and compared with those of the biomaterials with uniform porous structures based on the same type of the unit cell. The FGPB exhibited a low density (1.9 g/cm3), a moderate Young’s modulus (10.44 GPa), a high yield stress (170.6 MPa), a high maximum stress (201 MPa) and favorable ductility, being superior to the biomaterials with uniform porous structures in comprehensive mechanical properties. In addition, digital image correlation (DIC) and finite element (FE) simulation were used to unravel the mechanisms governing the deformation and yielding behavior of these biomaterials particularly at the strut junctions. Both DIC and FE simulations confirmed that the deformation and yielding of the FGPB occurred largely in the load-bearing layers but not at the interfaces between layers. Defect-coupled FE models based on solid elements provided further insights into the mechanical responses of the FGPB to compressive loads at both macro- and micro-scales. With the defect-coupled representative volume element model for the FGPB, the Young’s modulus and yield stress of the FGPBs were predicted with less than 2% deviations from the experimental data. The study clearly demonstrated the capabilities of combined experimental and computational methods to resolve the uncertainties of the mechanical behavior of FGPBs, which would open up the possibilities of applying various porosity variation strategies for the design of biomimetic AM porous biomaterials.
Functionally graded bone scaffolds significantly promote the recovery of segmental bone defect. In the present study, we present a step-wise topological design of functionally graded porous biomaterial (FGPB) to mimic the structure of the femoral diaphysis. The Ti-6Al-4V FGPB exhibited a superior combination of low density, moderate Young’s modulus, high yield stress and maximum stress as well as favorable ductility. The biomechanical performance of FGPB was studied in both macro and micro perspectives. The defect-coupled model revealed the significant yielding in the load-bearing parts and the Young’s modulus and yield stress of the FGPBs were predicted with less than 2% deviations from the experimental data. The superiority of combined experimental and computational methods has been confirmed.
Four-dimensional (4D) bioprinting, encompassing a wide range of disciplines including bioengineering, materials science, chemistry, and computer sciences, is emerging as the next-generation ...biofabrication technology. By utilizing stimuli-responsive materials and advanced three-dimensional (3D) bioprinting strategies, 4D bioprinting aims to create dynamic 3D patterned biological structures that can transform their shapes or behavior under various stimuli. In this review, we highlight the potential use of various stimuli-responsive materials for 4D printing and their extension into biofabrication. We first discuss the state of the art and limitations associated with current 3D printing modalities and their transition into the inclusion of the additional time dimension. We then suggest the potential use of different stimuli-responsive biomaterials as the bioink that may achieve 4D bioprinting where transformation of fabricated biological constructs can be realized. We finally conclude with future perspectives.
Bone regeneration involves various complex biological processes. Many experiments have been performed using biomaterials in vivo and in vitro to promote and understand bone regeneration. Among the ...many biomaterials, calcium phosphates which exist in the natural bone have been conducted a number of studies because of its bone regenerative property. It can be directly contributed to bone regeneration process or assist in the use of other biomaterials. Therefore, it is widely used in many applications and has been continuously studied.
Calcium phosphate has been widely used in bone regeneration applications because it shows osteoconductive and in some cases osteoinductive features. The release of calcium and phosphorus ions regulates the activation of osteoblasts and osteoclasts to facilitate bone regeneration. The control of surface properties and porosity of calcium phosphate affects cell/protein adhesion and growth and regulates bone mineral formation. Properties affecting bioactivity vary depending on the types of calcium phosphates such as HAP, TCP and can be utilized in various applications because of differences in ion release, solubility, stability, and mechanical strength. In order to make use of these properties, different calcium phosphates have been used together or mixed with other materials to complement their disadvantages and to highlight their advantages. Calcium phosphate has been utilized to improve bone regeneration in ways such as increasing osteoconductivity for bone ingrowth, enhancing osteoinductivity for bone mineralization with ion release control, and encapsulating drugs or growth factors.
Calcium phosphate has been used for bone regeneration in various forms such as coating, cement and scaffold based on its unique bioactive properties and bone regeneration effectiveness. Additionally, several studies have been actively carried out to improve the efficacy of calcium phosphate in combination with various healing agents. By summarizing the properties of calcium phosphate and its research direction, we hope that calcium phosphate can contribute to the clinical treatment approach for bone defect and disease.
In the field of orthopaedics, inflammation-modulatory biomaterials are receiving increasing attentions due to their abilities to regulate innate immune response and mediate wound healing. In the ...current work, a Cu-containing micro/nano-topographical bio-ceramic surface (Cu-Hier-Ti surface) was employed as material model to explore the role played by Cu2+ release or material surface in regulating macrophage polarization as well as macrophage-mediated osteogenic and bactericidal effect. A Cu-free micro-topographical surface (Micro-Ti surface) generated by micro-arc oxidation was employed as control. The results showed that Cu2+ supplemented directly into the culture medium or released from Cu-Hier-Ti surface could polarize macrophages to pro-inflammatory M1 phenotype by activating Cu-transport signaling (copper transporter 1 (CTR1) and ATP7A) in macrophages, while the material characteristics exhibited anti-inflammatory effect to some extent by regulating integrin (α5, αM, β1 and β2) and TLR (TLR-3, TLR-4, Myd88 and Ticam-1/2) signaling. Macrophages grown on Cu-Hier-Ti surface or treated by Cu2+ could create a favorable inflammatory microenvironment for osteoblast-like SaOS-2 cell proliferation and differentiation. Moreover, Cu-Hier-Ti surface promoted macrophage capacity to engulf and kill bacteria, even though it did not show direct bactericidal effect against Staphylococcus aureus. In vivo results showed that Cu-Hier-Ti surface could lead to promoted osteointegraion and enhanced expression levels of M1 surface marker CD11c, growth factor BMP-6 and osteogenic makers including osteocalcin (OCN) and Runx-2 at the biomaterial/bone tissue interface in a rat model. The results indicate that Cu could be employed as a promising inflammation-modulatory agent to activate macrophages for enhanced osteogenic and bactericidal effect.
The next generation of bone biomaterials should be active to regulate the local inflammatory environment such that it favors bone regeneration. For the design and development of Cu-containing inflammation-modulatory biomaterials, it is of great importance to recognize the exact role played by Cu2+ release or material surface characteristics. So far, relatively little is known about the regulatory role of Cu2+ or micro/nano-topographical surface on macrophages. The results in the current work suggest that Cu2+ release and material surface characteristics of Cu-containing micro/nano-topographical coating could activate distinct signaling pathways in macrophages. The activated M1 macrophages exhibited stimulatory effect on osteoblast maturation and enhanced bactericidal capacity against Staphylococcus aureus. This study might provide new thoughts for the development of multi-functional Cu-containing biomaterials.
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Native tissues orchestrate their functions by complex interdependent cascades of biochemical and biophysical cues that vary spatially and temporally during cellular processes. ...Scaffolds with well-tuned structural, mechanical, and biochemical properties have been developed to guide cell behavior and provide insight on cell-matrix interaction. However, static scaffolds very often fail to mimic the dynamicity of native extracellular matrices. Stimuli-responsive scaffolds have emerged as powerful platforms that capture vital features of native tissues owing to their ability to change chemical and physical properties in response to cytocompatible stimuli, thus enabling on-demand manipulation of cell microenvironment. The vast expansion in biorthogonal chemistries and stimuli-responsive functionalities has fuelled further the development of new smart scaffolds that can permit multiple irreversible or reversible spatiotemporal modulation of cell-directing cues, thereby prompting in-depth studies to interpret the decisive elements that regulate cell behavior. Integration of stimuli-responsive hydrogels with current biofabrication technologies has allowed the development of dynamic scaffolds with organizational features and hierarchical architectures similar to native tissues. This review highlights the progress achieved using stimuli-responsive hydrogels in fundamental cell biology studies, with particular emphasis on the interplay between chemistry, biomaterials design, and biofabrication technologies for manipulation of cell microenvironment.
Biomaterials play a critical role in engineering of tissue constructs, working as an artificial extracellular matrix to support regeneration. Because the elastic stretchability is a major mechanical ...property of many tissue types, huge efforts have been invested into the development of elastomeric biomaterials that mimic that of native tissue. Indeed, for the repair of most soft tissue types, one of the major problems encountered by biomaterials scientists has been difficulty in simply replicating this complex elasticity. This article provides a comprehensive review on the elastomeric biomaterials used in tissue engineering. Definitions of biomaterials, biocompatibility and elasticity in the context of tissue engineering are introduced. This is followed by systematic review of thermoplastic rubbers, chemically crosslinked elastomers, elastic proteins and elastomer-based ceramic-filled composites. Each section includes a detailed description of the chemical synthesis of the polymer critical to understanding of its unique properties, followed by discussion of its biocompatibility and biodegradability, two essential features of biomaterials in most tissue engineering applications. The mechanical properties and applications in tissue engineering are then reviewed for each polymer in great detail, with identification of specific challenges for its current and ongoing application in the field. Finally, the major achievements and remaining challenges for elastomeric biomaterials are summarized, with emphasis on the most important candidates to date.
Macrophages are a highly heterogeneous and plastic population of cells that are crucial for tissue repair and regeneration. This has made macrophages a particularly attractive target for ...biomaterial-directed regenerative medicine strategies. However, macrophages also contribute to adverse inflammatory and fibrotic responses to implanted biomaterials, typically related to the foreign body response (FBR). The traditional model in the field asserts that the M2 macrophage phenotype is pro-regenerative and associated with positive wound healing outcomes, whereas the M1 phenotype is pro-inflammatory and associated with pathogenesis. However, recent studies indicate that both M1 and M2 macrophages play different, but equally vital, roles in promoting tissue repair. Furthermore, recent technological developments such as single-cell RNA sequencing have allowed for unprecedented insights into the heterogeneity within the myeloid compartment, related to activation state, niche, and ontogenetic origin. A better understanding of the phenotypic and functional characteristics of macrophages critical to tissue repair and FBR processes will allow for rational design of biomaterials to promote biomaterial-tissue integration and regeneration. In this review, we discuss the role of temporal and ontogenetic macrophage heterogeneity on tissue repair processes and the FBR and the potential implications for biomaterial-directed regenerative medicine applications.
This review outlines the contributions of different macrophage phenotypes to different phases of wound healing and angiogenesis. Pathological outcomes, such as chronic inflammation, fibrosis, and the foreign body response, related to disruption of the macrophage inflammation-resolution process are also discussed. We summarize recent insights into the vast heterogeneity of myeloid cells related to their niche, especially the biomaterial microenvironment, and ontogenetic origin. Additionally, we present a discussion on novel tools that allow for resolution of cellular heterogeneity at the single-cell level and how these can be used to build a better understanding of macrophage heterogeneity in the biomaterial immune microenvironment to better inform immunomodulatory biomaterial design.
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For treatment of bone tumor and regeneration of bone defects, the biomaterials should possess the ability to kill tumor cells and regenerate bone defect simultaneously. To date, there ...are a few biomaterials possessing such dual functions, the disadvantages, however, such as long-term toxicity and degradation, restrict their application. Although bioactive elements have been incorporated into biomaterials to improve their osteogenic activity, there is no report about elements-induced functional scaffolds for photothermal tumor therapy. Herein, the elements (Cu, Fe, Mn, Co)-doped bioactive glass-ceramic (BGC) scaffolds with photothermal effect and osteogenic differentiation ability were prepared via 3D-printing method. Moreover, the photothermal anti-tumor effect and osteogenic activity of these scaffolds were systematically investigated. The prepared elements-doped scaffolds possessed excellent photothermal performance, which displayed a trend, 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC, in this study. The final temperature of elements-doped scaffolds can be well controlled by altering the doping element categories, contents and laser power density. Additionally, the hyperthermia induced by 5Cu-BGC, 5Fe-BGC and 5Mn-BGC effectively killed tumor cells in vitro and inhibited tumor growth in vivo. More importantly, 5Fe-BGC and 5Mn-BGC scaffolds could promote rabbit bone mesenchymal stem cells (rBMSCs) adhesion, and the ionic products released from elements-doped scaffolds significantly stimulated the osteogenic differentiation of bone-forming cells. These results suggested that 5Fe-BGC and 5Mn-BGC scaffolds possessed promising potential for photothermal treatment of bone tumor and at the same time for stimulating bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds.
The major innovation of this study is that we fabricated the elements (Cu, Fe, Mn, Co)-doped bioactive scaffolds via 3D printing technique and found that they possess distinct photothermal performance and osteogenic differentiation ability. To the best of our knowledge, there is no report about elements-doped scaffolds for photothermal therapy of bone tumor. This is an important research advance by combining the photothermal effect and osteogenic differentiation activity of bioactive elements in the scaffold system for potential bone tumor therapy and bone reconstruction. We optimized the elements-doped scaffolds and found the photothermal effect of elements-doped scaffolds (5Cu-BGC, 5Fe-BGC, 5Mn-BGC) could effectively kill tumor cells in vivo. The photothermal performance of elements-doped scaffolds follows a trend: 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC > BGC. Compared to traditional nano-sized photothermal agents, bioactive elements-induced functional scaffolds have better biosecurity and bioactivity. Furthermore, 5Fe-BGC and 5Mn-BGC scaffolds displayed excellent bone-forming activity by stimulating the osteogenic differentiation of bone-forming cells. The major significance of the study is that the elements-doped bioactive glass-ceramics (5Fe-BGC, 5Mn-BGC) have great potential to be used as bifunctional scaffolds for photothermal tumor therapy and bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds.
Arginine‐glycine‐aspartic acid (RGD) peptide family is known as the most prominent ligand for extracellular domain of integrin receptors. Specific expression of these receptors in various tissue of ...human body and tight association of their expression profile with various pathophysiological conditions made these receptors a suitable targeting candidate for several disease diagnosis and treatment as well as regeneration of various organs. For these reasons, various forms of RGD‐based integrins ligands have been greatly used in biomedical studies. Here, we summarized the last decade application progress of RGD for cancer theranostics, control of inflammation, thrombosis inhibition and critically discussed the effect of RGD peptides structure and sequence on the efficacy of gene/drug delivery systems in preclinical studies. Furthermore, we will show recent advances in application of RGD functionalized biomaterials for various tissue regenerations including cornea repair, artificial neovascularization and bone tissue regeneration. Finally, we analyzed clinically translatability of RGD peptides, considering examples of integrin ligands in clinical trials. In conclusion, prospects on using RGD peptide for precise drug delivery and biomaterial engineering are well discussed.
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