Customized scaffolds for large bone defects using 3D‑printed modular blocks from 2D‑medical images

Additive manufacturing(AM)has revolutionized the design and manufacturing of patient-specific,three-dimensional(3D),complex porous structures known as scaffolds for tissue engineering applications.The use of advanced image acquisition techniques,image processing,and computer-aided design methods has enabled the precise design and additive manufacturing of anatomically correct and patient-specific implants and scaffolds.However,these sophisticated techniques can be timeconsuming,labor-intensive,and expensive.Moreover,the necessary imaging and manufacturing equipment may not be readily available when urgent treatment is needed for trauma patients.In this study,a novel design and AM methods are proposed for the development of modular and customizable scaffold blocks that can be adapted to fit the bone defect area of a patient.These modular scaffold blocks can be combined to quickly form any patient-specific scaffold directly from two-dimensional(2D)medical images when the surgeon lacks access to a 3D printer or cannot wait for lengthy 3D imaging,modeling,and 3D printing during surgery.The proposed method begins with developing a bone surface-modeling algorithm that reconstructs a model of the patient’s bone from 2D medical image measurements without the need for expensive 3D medical imaging or segmentation.This algorithm can generate both patient-specific and average bone models.Additionally,a biomimetic continuous path planning method is developed for the additive manufacturing of scaffolds,allowing porous scaffold blocks with the desired biomechanical properties to be manufactured directly from 2D data or images.The algorithms are implemented,and the designed scaffold blocks are 3D printed using an extrusion-based AM process.Guidelines and instructions are also provided to assist surgeons in assembling scaffold blocks for the self-repair of patient-specific large bone defects.

Long-term efficacy,safety and biocompatibility of a novel sirolimus eluting iron bioresorbable scaffold in a porcine model

Iron is considered as an attractive alternative material for bioresorbable scaffolds(BRS).The sirolimus eluting iron bioresorbable scaffold(IBS),developed by Biotyx Medical(Shenzhen,China),is the only iron-based BRS with an ultrathin-wall design.The study aims to investigate the long-term efficacy,safety,biocompatibility,and lumen changes during the biodegradation process of the IBS in a porcine model.A total of 90 IBSs and 70 cobaltchromium everolimus eluting stents(EES)were randomly implanted into nonatherosclerotic coronary artery of healthy mini swine.The multimodality assessments including coronary angiography,optical coherence tomography,micro-computed tomography,magnetic resonance imaging,real-time polymerase chain reaction(PCR),and histopathological evaluations,were performed at different time points.There was no statistical difference in area stenosis between IBS group and EES group at 6 months,1year,2 years and 5 years.Although the scaffolded vessels narrowed at 9 months,expansive remodeling with increased mean lumen area was found at 3 and 5 years.The IBS struts remained intact at 6 months,and the corrosion was detectable at 9 months.At 5 years,the iron struts were completely degraded and absorbed in situ,without in-scaffold restenosis or thrombosis,lumen collapse,aneurysm formation,and chronic inflammation.No local or systemic toxicity and abnormal histopathologic manifestation were found in all experiments.Results from real-time PCR indicated that no sign of iron overload was reported in scaffolded segments.Therefore,the IBS shows comparable efficacy,safety,and biocompatibility with EES,and late lumen enlargement is considered as a unique feature in the IBS-implanted vessels.

Biological scaffold as potential platforms for stem cells:Current development and applications in wound healing

Wound repair is a complex challenge for both clinical practitioners and researchers.Conventional approaches for wound repair have several limitations.Stem cell-based therapy has emerged as a novel strategy to address this issue,exhibiting significant potential for enhancing wound healing rates,improving wound quality,and promoting skin regeneration.However,the use of stem cells in skin regeneration presents several challenges.Recently,stem cells and biomaterials have been identified as crucial components of the wound-healing process.Combination therapy involving the development of biocompatible scaffolds,accompanying cells,multiple biological factors,and structures resembling the natural extracellular matrix(ECM)has gained considerable attention.Biological scaffolds encompass a range of biomaterials that serve as platforms for seeding stem cells,providing them with an environment conducive to growth,similar to that of the ECM.These scaffolds facilitate the delivery and application of stem cells for tissue regeneration and wound healing.This article provides a comprehensive review of the current developments and applications of biological scaffolds for stem cells in wound healing,emphasizing their capacity to facilitate stem cell adhesion,proliferation,differentiation,and paracrine functions.Additionally,we identify the pivotal characteristics of the scaffolds that contribute to enhanced cellular activity.

Insights into Nano-and Micro-Structured Scaffolds for Advanced Electrochemical Energy Storage

Adopting a nano-and micro-structuring approach to fully unleashing the genuine potential of electrode active material benefits in-depth understandings and research progress toward higher energy density electrochemical energy stor-age devices at all technology readiness levels.Due to various challenging issues,especially limited stability,nano-and micro-structured(NMS)electrodes undergo fast electrochemical performance degradation.The emerging NMS scaffold design is a pivotal aspect of many electrodes as it endows them with both robustness and electrochemical performance enhancement,even though it only occupies comple-mentary and facilitating components for the main mechanism.However,extensive efforts are urgently needed toward optimizing the stereoscopic geometrical design of NMS scaffolds to minimize the volume ratio and maximize their functionality to fulfill the ever-increasing dependency and desire for energy power source supplies.This review will aim at highlighting these NMS scaffold design strategies,summariz-ing their corresponding strengths and challenges,and thereby outlining the potential solutions to resolve these challenges,design principles,and key perspectives for future research in this field.Therefore,this review will be one of the earliest reviews from this viewpoint.

Constructing a biofunctionalized 3D-printed gelatin/sodium alginate/chitosan tri-polymer complex scaffold with improvised biological andmechanical properties for bone-tissue engineering

Sodium alginate(SA)/chitosan(CH)polyelectrolyte scaffold is a suitable substrate for tissue-engineering application.The present study deals with further improvement in the tensile strength and biological properties of this type of scaffold to make it a potential template for bone-tissue regeneration.We experimented with adding 0%–15%(volume fraction)gelatin(GE),a protein-based biopolymer known to promote cell adhesion,proliferation,and differentiation.The resulting tri-polymer complex was used as bioink to fabricate SA/CH/GEmatrices by three-dimensional(3D)printing.Morphological studies using scanning electron microscopy revealed the microfibrous porous architecture of all the structures,which had a pore size range of 383–419μm.X-ray diffraction and Fourier-transform infrared spectroscopy analyses revealed the amorphous nature of the scaffold and the strong electrostatic interactions among the functional groups of the polymers,thereby forming polyelectrolyte complexes which were found to improve mechanical properties and structural stability.The scaffolds exhibited a desirable degradation rate,controlled swelling,and hydrophilic characteristics which are favorable for bone-tissue engineering.The tensile strength improved from(386±15)to(693±15)kPa due to the increased stiffness of SA/CH scaffolds upon addition of gelatin.The enhanced protein adsorption and in vitro bioactivity(forming an apatite layer)confirmed the ability of the SA/CH/GE scaffold to offer higher cellular adhesion and a bone-like environment to cells during the process of tissue regeneration.In vitro biological evaluation including the MTT assay,confocal microscopy analysis,and alizarin red S assay showed a significant increase in cell attachment,cell viability,and cell proliferation,which further improved biomineralization over the scaffold surface.In addition,SA/CH containing 15%gelatin designated as SA/CH/GE15 showed superior performance to the other fabricated 3D structures,demonstrating its potential for use in bone-tissue engineering.

3D-printed Mg-1Ca/polycaprolactone composite scaffolds with promoted bone regeneration

In bone tissue engineering,polycaprolactone(PCL)is a promising material with good biocompatibility,but its poor degradation rate,mechanical strength,and osteogenic properties limit its application.In this study,we developed an Mg-1Ca/polycaprolactone(Mg-1Ca/PCL)composite scaffolds to overcome these limitations.We used a melt blending method to prepare Mg-1Ca/PCL composites with Mg-1Ca alloy powder mass ratios of 5,10,and 20 wt%.Porous scaffolds with controlled macro-and microstructure were printed using the fused deposition modeling method.We explored the mechanical strength,biocompatibility,osteogenesis performance,and molecular mechanism of the Mg-1Ca/PCL composites.The 5 and 10 wt%Mg-1Ca/PCL composites were found to have good biocompatibility.Moreover,they promoted the mechanical strength,proliferation,adhesion,and osteogenic differentiation of human bone marrow stem cells(hBMSCs)of pure PCL.In vitro degradation experiments revealed that the composite material stably released Mg_(2)+ions for a long period;it formed an apatite layer on the surface of the scaffold that facilitated cell adhesion and growth.Microcomputed tomography and histological analysis showed that both 5 and 10 wt%Mg-1Ca/PCL composite scaffolds promoted bone regeneration bone defects.Our results indicated that the Wnt/β-catenin pathway was involved in the osteogenic effect.Therefore,Mg-1Ca/PCL composite scaffolds are expected to be a promising bone regeneration material for clinical application.Statement of significance:Bone tissue engineering scaffolds have promising applications in the regeneration of critical-sized bone defects.However,there remain many limitations in the materials and manufacturing methods used to fabricate scaffolds.This study shows that the developed Ma-1Ca/PCL composites provides scaffolds with suitable degradation rates and enhanced boneformation capabilities.Furthermore,the fused deposition modeling method allows precise control of the macroscopic morphology and microscopic porosity of the scaffold.The obtained porous scaffolds can significantly promote the regeneration of bone defects.

In vitro investigations on the effects of graphene and graphene oxide on polycaprolactone bone tissue engineering scaffolds

Polycaprolactone(PCL)scaffolds that are produced through additive manufacturing are one of the most researched bone tissue engineering structures in the field.Due to the intrinsic limitations of PCL,carbon nanomaterials are often investigated to reinforce the PCL scaffolds.Despite several studies that have been conducted on carbon nanomaterials,such as graphene(G)and graphene oxide(GO),certain challenges remain in terms of the precise design of the biological and nonbiological properties of the scaffolds.This paper addresses this limitation by investigating both the nonbiological(element composition,surface,degradation,and thermal and mechanical properties)and biological characteristics of carbon nanomaterial-reinforced PCL scaffolds for bone tissue engineering applications.Results showed that the incorporation of G and GO increased surface properties(reduced modulus and wettability),material crystallinity,crystallization temperature,and degradation rate.However,the variations in compressive modulus,strength,surface hardness,and cell metabolic activity strongly depended on the type of reinforcement.Finally,a series of phenomenological models were developed based on experimental results to describe the variations of scaffold’s weight,fiber diameter,porosity,and mechanical properties as functions of degradation time and carbon nanomaterial concentrations.The results presented in this paper enable the design of three-dimensional(3D)bone scaffolds with tuned properties by adjusting the type and concentration of different functional fillers.

Coaxial electrohydrodynamic printing of core–shell microfibrous scaffolds with layer-specific growth factors release for enthesis regeneration

The rotator cuff tear has emerged as a significant global health concern.However,existing therapies fail to fully restore the intricate bone-to-tendon gradients,resulting in compromised biomechanical functionalities of the reconstructed enthesis tissues.Herein,a tri-layered core–shell microfibrous scaffold with layer-specific growth factors(GFs)release is developed using coaxial electrohydrodynamic(EHD)printing for in situ cell recruitment and differentiation to facilitate gradient enthesis tissue repair.Stromal cell-derived factor-1(SDF-1)is loaded in the shell,while basic fibroblast GF,transforming GF-beta,and bone morphogenetic protein-2 are loaded in the core of the EHD-printed microfibrous scaffolds in a layer-specific manner.Correspondingly,the tri-layered microfibrous scaffolds have a core–shell fiber size of(25.7±5.1)μm,with a pore size sequentially increasing from(81.5±4.6)μm to(173.3±6.9)μm,and to(388.9±6.9μm)for the tenogenic,chondrogenic,and osteogenic instructive layers.A rapid release of embedded GFs is observed within the first 2 d,followed by a faster release of SDF-1 and a slightly slower release of differentiation GFs for approximately four weeks.The coaxial EHD-printed microfibrous scaffolds significantly promote stem cell recruitment and direct their differentiation toward tenocyte,chondrocyte,and osteocyte phenotypes in vitro.When implanted in vivo,the tri-layered core–shell microfibrous scaffolds rapidly restored the biomechanical functions and promoted enthesis tissue regeneration with native-like bone-to-tendon gradients.Our findings suggest that the microfibrous scaffolds with layer-specific GFs release may offer a promising clinical solution for enthesis regeneration.

Developing fibrin-based biomaterials/scaffolds in tissue engineering

Tissue engineering technology has advanced rapidly in recent years, offering opportunities to construct biologicallyactive tissues or organ substitutes to repair or even enhance the functions of diseased tissues and organs.Tissue-engineered scaffolds rebuild the extracellular microenvironment by mimicking the extracellular matrix.Fibrin-based scaffolds possess numerous advantages, including hemostasis, high biocompatibility, and gooddegradability. Fibrin scaffolds provide an initial matrix that facilitates cell migration, differentiation, proliferation,and adhesion, and also play a critical role in cell-matrix interactions. Fibrin scaffolds are now widelyrecognized as a key component in tissue engineering, where they can facilitate tissue and organ defect repair.This review introduces the properties of fibrin, including its composition, structure, and biology. In addition, themodification and cross-linking modes of fibrin are discussed, along with various forms commonly used in tissueengineering. We also describe the biofunctionalization of fibrin. This review provides a detailed overview of theuse and applications of fibrin in skin, bone, and nervous tissues, and provides novel insights into future researchdirections for clinical treatment.

Oxygen vacancy boosting Fenton reaction in bone scaffold towards fighting bacterial infection

Bacterial infection is a major issue after artificial bone transplantation due to the absence of antibacterial function of bone scaffold,which seriously causes the transplant failure and even amputation in severe cases.In this study,oxygen vacancy(OV)defects Fe-doped Ti O2(OV-FeTiO2)nanoparticles were synthesized by nano TiO2and Fe3O4via high-energy ball milling,which was then incorporated into polycaprolactone/polyglycolic acid(PCLGA)biodegradable polymer matrix to construct composite bone scaffold with good antibacterial activities by selective laser sintering.The results indicated that OV defects were introduced into the core/shell-structured OV-FeTiO2nanoparticles through multiple welding and breaking during the high-energy ball milling,which facilitated the adsorption of hydrogen peroxide(H2O2)in the bacterial infection microenvironment at the bone transplant site.The accumulated H2O2could amplify the Fenton reaction efficiency to induce more hydroxyl radicals(·OH),thereby resulting in more bacterial deaths through·OH-mediated oxidative damage.This antibacterial strategy had more effective broad-spectrum antibacterial properties against Gram-negative Escherichia coli(E.coli)and Gram-positive Staphylococcus aureus(S.aureus).In addition,the PCLGA/OV-FeTiO2scaffold possessed mechanical properties that match those of human cancellous bone and good biocompatibility including cell attachment,proliferation and osteogenic differentiation.

Orthogonally woven 3D nanofiber scaffolds promote rapid soft tissue regeneration by enhancing bidirectional cell migration

Repairing large-area soft tissue defects caused by traumas is a major surgical challenge.Developing multifunctional scaffolds with suitable scalability and favorable cellular response is crucial for soft tissue regeneration.In this study,we developed an orthogonally woven three-dimensional(3D)nanofiber scaffold combining electrospinning,weaving,and modified gas-foaming technology.The developed orthogonally woven 3D nanofiber scaffold had a modular design and controlled fiber alignment.In vitro,the orthogonally woven 3D nanofiber scaffold exhibited adjustable mechanical properties,good cell compatibility,and easy drug loading.In vivo,for one thing,the implantation of an orthogonally woven 3D nanofiber scaffold in a full abdominal wall defect model demonstrated that extensive granulation tissue formation with enough mechanical strength could promote recovery of abdominal wall defects while reducing intestinal adhesion.Another result of diabetic wound repair experiments suggested that orthogonally woven 3D nanofiber scaffolds had a higher wound healing ratio,granulation tissue formation,collagen deposition,and re-epithelialization.Taken together,this novel orthogonally woven 3D nanofiber scaffold may provide a promising and effective approach for optimal soft tissue regeneration.

Advanced strategies for 3D-printed neural scaffolds:materials,structure,and nerve remodeling

Nerve regeneration holds significant potential in the treatment of various skeletal and neurological disorders to restore lost sensory and motor functions.The potential of nerve regeneration in ameliorating neurological diseases and injuries is critical to human health.Three-dimensional(3D)printing offers versatility and precision in the fabrication of neural scaffolds.Complex neural structures such as neural tubes and scaffolds can be fabricated via 3Dprinting.This reviewcomprehensively analyzes the current state of 3D-printed neural scaffolds and explores strategies to enhance their design.It highlights therapeutic strategies and structural design involving neural materials and stem cells.First,nerve regeneration materials and their fabrication techniques are outlined.The applications of conductive materials in neural scaffolds are reviewed,and their potential to facilitate neural signal transmission and regeneration is highlighted.Second,the progress in 3D-printed neural scaffolds applied to the peripheral and central nerves is comprehensively evaluated,and their potential to restore neural function and promote the recovery of different nervous systems is emphasized.In addition,various applications of 3D-printed neural scaffolds in peripheral and neurological diseases,as well as the design strategies of multifunctional biomimetic scaffolds,are discussed.

Enhanced axonal regeneration and functional recovery of the injured sciatic nerve in a rat model by lithium-loaded electrospun nanofibrous scaffolds

Increasing evidence indicates that engineered nerve grafts have great potential for the regeneration of peripheral nerve injuries(PNIs).While most studies have focused only on the topographical features of the grafts,we have considered both the biophysical and biochemical manipulations in our applied nanoscaffold.To achieve this,we fabricated an electrospun nanofibrous scaffold(ENS)containing polylactide nanofibers loaded with lithium(Li)ions,a Wnt/β-catenin signaling activator.In addition,we seeded human adipose-derived mesenchymal stem cells(hADMSCs)onto this engineered scaffold to examine if their differentiation toward Schwann-like cells was induced.We further examined the efficacy of the scaffolds for nerve regeneration in vivo via grafting in a PNI rat model.Our results showed that Li-loaded ENSs gradually released Li within 11 d,at concentrations ranging from 0.02 to(3.64±0.10)mmol/L,and upregulated the expression of Wnt/β-catenin target genes(cyclinD1 and c-Myc)as well as those of Schwann cell markers(growth-associated protein 43(GAP43),S100 calcium binding protein B(S100B),glial fibrillary acidic protein(GFAP),and SRY-box transcription factor 10(SOX10))in differentiated hADMSCs.In the PNI rat model,implantation of Li-loaded ENSs with/without cells improved behavioral features such as sensory and motor functions as well as the electrophysiological characteristics of the injured nerve.This improved function was further validated by histological analysis of sciatic nerves grafted with Li-loaded ENSs,which showed no fibrous connective tissue but enhanced organized myelinated axons.The potential of Li-loaded ENSs in promoting Schwann cell differentiation of hADMSCs and axonal regeneration of injured sciatic nerves suggests their potential for application in peripheral nerve tissue engineering.

Numerical Analysis of Permeability of Functionally Graded Scaffolds

In this work,we numerically study the hydrodynamic permeability of new-generation artificial porous materials used as scaffolds for cell growth in a perfusion bioreactor.We consider two popular solid matrix designs based on triply periodic minimal surfaces,the Schwarz P(primitive)and D(diamond)surfaces,which enable the creation of materials with controlled porosity gradients.The latter property is crucial for regulating the shear stress field in the pores of the scaffold,which makes it possible to control the intensity of cell growth.The permeability of functionally graded materials is studied within the framework of both a microscopic approach based on the Navier-Stokes equation and an averaged description of the liquid filtration through a porous medium based on the equations of the Darcy or Forchheimer models.We calculate the permeability coefficients for both types of solid matrices formed by Schwarz surfaces,study their properties concerning forward and reverse fluid flows,and determine the ranges of Reynolds number for which the description within the Darcy or Forchheimer model is applicable.Finally,we obtain a shear stress field that varies along the sample,demonstrating the ability to tune spatially the rate of tissue growth.

Ag-doped CNT/HAP nanohybrids in a PLLA bone scaffold show significant antibacterial activity

Bacterial infection is a major problem following bone implant surgery.Moreover,poly-l-lactic acid/carbon nanotube/hydroxyapatite(PLLA/CNT/HAP)bone scaffolds possess enhanced mechanical properties and show good bioactiv-ityregardingbonedefectregeneration.Inthisstudy,wesynthesizedsilver(Ag)-dopedCNT/HAP(CNT/Ag-HAP)nanohybrids via the partial replacing of calcium ions(Ca2+)in the HAP lattice with silver ions(Ag+)using an ion doping technique under hydrothermal conditions.Specifically,the doping process was induced using the special lattice structure of HAP and the abundant surface oxygenic functional groups of CNT,and involved the partial replacement of Ca2+in the HAP lattice by doped Ag+as well as the in situ synthesis of Ag-HAP nanoparticles on CNT in a hydrothermal environment.The result-ing CNT/Ag-HAP nanohybrids were then introduced into a PLLA matrix via laser-based powder bed fusion(PBF-LB)to fabricate PLLA/CNT/Ag-HAP scaffolds that showed sustained antibacterial activity.We then found that Ag+,which pos-sesses broad-spectrum antibacterial activity,endowed PLLA/CNT/Ag-HAP scaffolds with this activity,with an antibacterial effectiveness of 92.65%.This antibacterial effect is due to the powerful effect of Ag+against bacterial structure and genetic material,as well as the physical destruction of bacterial structures due to the sharp edge structure of CNT.In addition,the scaffold possessed enhanced mechanical properties,showing tensile and compressive strengths of 8.49 MPa and 19.72 MPa,respectively.Finally,the scaffold also exhibited good bioactivity and cytocompatibility,including the ability to form apatite layers and to promote the adhesion and proliferation of human osteoblast-like cells(MG63 cells).

Creating a bionic scaffold via light-curing liquid crystal ink to reveal the role of osteoid-like microenvironment in osteogenesis

Osteoid plays a crucial role in directing cell behavior and osteogenesis through its unique characteristics,including viscoelasticity and liquid crystal(LC)state.Thus,integrating osteoid-like features into 3D printing scaffolds proves to be a promising approach for personalized bone repair.Despite extensive research on viscoelasticity,the role of LC state in bone repair has been largely overlooked due to the scarcity of suitable LC materials.Moreover,the intricate interplay between LC state and viscoelasticity in osteogenesis remains poorly understood.Here,we developed innovative hydrogel scaffolds with osteoid-like LC state and viscoelasticity using digital light processing with a custom LC ink.By utilizing these LC scaffolds as 3D research models,we discovered that LC state mediates high protein clustering to expose accessible RGD motifs to trigger cell-protein interactions and osteogenic differentiation,while viscoelasticity operates via mechanotransduction pathways.Additionally,our investigation revealed a synergistic effect between LC state and viscoelasticity,amplifying cellprotein interactions and osteogenic mechanotransduction processes.Furthermore,the interesting mechanochromic response observed in the LC hydrogel scaffolds suggests their potential application in mechanosensing.Our findings shed light on the mechanisms and synergistic effects of LC state and viscoelasticity in osteoid on osteogenesis,offering valuable insights for the biomimetic design of bone repair scaffolds.

Flame Retardant Material Based on Cellulose Scaffold Mineralized by Calcium Carbonate

Wood-based functional materials have developed rapidly.But the flammability significantly limits its further application.To improve the flame retardancy,the balsa wood was delignified by NaClO2 solution to create a cellulose scaffold,and then alternately immersed in CaCl_(2) ethanol solution and NaHCO3 aqueous solution under vacuum.The high porosity and wettability resulting from delignification benefited the following mineralization process,changing the thermal properties of balsa wood significantly.The organic-inorganic wood composite showed abundant CaCO_(3) spherical particles under scanning electron microscopy.The peak of the heat release rate of delignified balsa-CaCO_(3) was reduced by 33%compared to the native balsa,according to the cone calorimetric characterization.The flame test demonstrated that the mineralized wood was flame retardant and selfextinguish.Additionally,the mineralized wood also displayed lower thermal conductivity.This study developed a feasible way to fabricate a lightweight,fire-retardant,self-extinguishing,and heat-insulating wood composite,providing a promising route for the valuable application of cellulosic biomass.

Recognizing and preventing complications regarding bioresorbable scaffolds during coronary interventions

The evolution of coronary intervention techniques and equipment has led to more sophisticated procedures for the treatment of highly complex lesions.However,as a result,the risk of complications has increased,which are mostly iatrogenic and often include equipment failure.Stent dislodgement warrants vigilance for the early diagnosis and a stepwise management approach is required to either expand or retrieve the lost stent.In the era of bioresorbable scaffolds that are not radiopaque,increased caution is required.Intravascular imaging may assist in detecting the lost scaffold in cases of no visibility fluoroscopically.Adequate lesion preparation is the key to minimizing the possibility of equipment loss;however,in the case that it occurs,commercially available and improvised devices and techniques may be applied.

3D/4D printed bio-piezoelectric smart scaffolds for next-generation bone tissue engineering

Piezoelectricity in native bones has been well recognized as the key factor in bone regeneration.Thus,bio-piezoelectric materials have gained substantial attention in repairing damaged bone by mimicking the tissue’s electrical microenvironment(EM).However,traditional manufacturing strategies still encounter limitations in creating personalized bio-piezoelectric scaffolds,hindering their clinical applications.Three-dimensional(3D)/four-dimensional(4D)printing technology based on the principle of layer-by-layer forming and stacking of discrete materials has demonstrated outstanding advantages in fabricating bio-piezoelectric scaffolds in a more complex-shaped structure.Notably,4D printing functionality-shifting bio-piezoelectric scaffolds can provide a time-dependent programmable tissue EM in response to external stimuli for bone regeneration.In this review,we first summarize the physicochemical properties of commonly used bio-piezoelectric materials(including polymers,ceramics,and their composites)and representative biological findings for bone regeneration.Then,we discuss the latest research advances in the 3D printing of bio-piezoelectric scaffolds in terms of feedstock selection,printing process,induction strategies,and potential applications.Besides,some related challenges such as feedstock scalability,printing resolution,stress-to-polarization conversion efficiency,and non-invasive induction ability after implantation have been put forward.Finally,we highlight the potential of shape/property/functionality-shifting smart 4D bio-piezoelectric scaffolds in bone tissue engineering(BTE).Taken together,this review emphasizes the appealing utility of 3D/4D printed biological piezoelectric scaffolds as next-generation BTE implants.

Three-dimensional kagome structures in a PCL/HA-based hydrogel scaffold to lead slow BMP-2 release for effective bone regeneration

Osteoconductive function is remarkably low in bone disease in the absence of bone tissue surrounding the grafting site,or if the bone tissue is in poor condition.Thus,an effective bone graft in terms of both osteoconductivity and osteoinductivity is required for clinical therapy.Recently,the three-dimensional(3D)kagome structure has been shown to be advantageous for bone tissue regeneration due to its mechanical properties.In this study,a polycaprolactone(PCL)kagome-structure scaffold containing a hyaluronic acid(HA)-based hydrogel was fabricated using a 3D printing technique.The retention capacity of the hydrogel in the scaffold was assessed in vivo with a rat calvaria subcutaneous model for 3 weeks,and the results were compared with those obtained with conventional 3D-printed PCL grid-structure scaffolds containing HA-based hydrogel and bulk-type HA-based hydrogel.The retained hydrogel in the kagome-structure scaffold was further evaluated by in vivo imaging system analysis.To further reinforce the osteoinductivity of the kagome-structure scaffold,a PCL kagome-structure scaffold with bone morphogenetic protein-2(BMP-2)containing HA hydrogel was fabricated and implanted in a calvarial defect model of rabbits for 16 weeks.The bone regeneration characteristics were evaluated with hematoxylin and eosin(H&E),Masson’s trichrome staining,and micro-CT image analysis.