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The treatment of osteoporotic bone defects poses a challenge due to the degradation of the skeletal vascular system and the disruption of local bone metabolism within the osteoporotic microenvironment. However, it is feasible to modulate the disrupted local bone metabolism imbalance through enhanced vascularization, a theory termed "vascularization-bone metabolic balance". This study developed a 3D-printed polycaprolactone (PCL) scaffold modified with EPLQLKM and SVVYGLR peptides (PCL-SE). The EPLQLKM peptide attracts bone marrow-derived mesenchymal stem cells (BMSCs), while the SVVYGLR peptide enhances endothelial progenitor cells (EPCs) vascular differentiation, thus regulating bone metabolism and fostering bone regeneration through the paracrine effects of EPCs. Further mechanistic research demonstrated that PCL-SE promoted the vascularization of EPCs, activating the Notch signaling pathway in BMSCs, leading to the upregulation of osteogenesis-related genes and the downregulation of osteoclast-related genes, thereby restoring bone metabolic balance. Furthermore, PCL-SE facilitated the differentiation of EPCs into "H"-type vessels and the recruitment of BMSCs to synergistically enhance osteogenesis, resulting in the regeneration of normal microvessels and bone tissues in cases of femoral condylar bone defects in osteoporotic SD rats. This study suggests that PCL-SE supports in-situ vascularization, remodels bone metabolic translational balance, and offers a promising therapeutic regimen for osteoporotic bone defects., Competing Interests: Declaration of competing interest The author has no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tissue regeneration/fibrosis after injury is intricately regulated by the immune cascade reaction and extracellular matrix (ECM). Dysregulated cascade signal could jeopardize tissue homeostasis leading to fibrosis. Bioactive scaffolds mimicking natural ECM microstructure and chemistry could regulate the cascade reaction to achieve tissue regeneration. The current study constructed an ECM-engineered micro/nanofibrous scaffold using self-assembled nanofibrous collagen and decorin (DCN)-loaded microfibers to regulate the immune cascade reaction. The ECM-engineered scaffold promoted anti-inflammatory and pro-regenerative effects, M2 polarization of macrophages, by nanofibrous collagen. The ECM-engineered scaffold could release DCN to inhibit inflammation-associated fibrous angiogenesis. Yet, to prevent excessive M2 activity leading to tissue fibrosis, controlled release of DCN was expected to elicit M1 activity and achieve M1/M2 balance in the repair process. Regulated cascade reaction guided favorable crosstalk between macrophages, endothelial cells and fibroblasts by proximity. Additionally, decorin could also antagonize TGF-β1 via TGF-β/Smad3 pathway to suppress fibrotic activity of fibroblasts. Hence, ECM-engineered scaffolds could exert effective regulation of the immune cascade reaction by microstructure and DCN release and achieve the balance between tissue fibrosis and regeneration. STATEMENT OF SIGNIFICANCE: With the incidence of up to 74.6%, failed back surgery syndrome (FBSS) has been a lingering issue in spine surgery, which poses a heavy socio-economic burden to society. Epidural fibrosis is believed to be responsible for the onset of FBSS. Current biomaterial-based strategies treating epidural fibrosis mainly rely on physical barriers and unidirectional suppression of inflammation. Regulation of the immune cascade reaction for inhibiting fibrosis has not been widely studied. Based on the simultaneous regulation of M1/M2 polarization and intercellular crosstalk, the ECM-engineered micro/nanofibrous scaffolds constructed in the current study could exert an immune cascade effect to coordinate tissue regeneration and inhibit fibrosis. This finding makes a significant contribution in the development of a treatment for epidural fibrosis and FBSS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Overexpression of inflammatory cytokines and chemokines occurs at deep soft tissue injury sites impeding the inflammation self-limiting and impairing the tissue remodeling process. Inspired by the electrostatically extracellular matrix (ECM) binding property of the inflammatory signals, an inflammation self-limiting fibrous tape is designed by covalently modifying the thermosensitive methacrylated gelatin (GelMA) and negatively charged methacrylated heparin (HepMA) hydrogel mixture with proper ratio onto the electrospun fibrous membrane by mild alkali hydrolysis and carboxyl-amino condensation reaction to restore inflammation self-limiting and promote tissue repair via regional immunity regulation. While the GelMA guarantees cell compatibility, the negatively charged HepMA successfully adsorbs the inflammatory cytokines and chemokines by electrostatic interactions and inhibits immune cell migration in vitro. Furthermore, in vivo inflammation self-limiting and regional immunity regulation efficacy is evaluated in a rat abdominal hernia model. Reduced local inflammatory cytokines and chemokines in the early stage and increased angiogenesis and ECM remodeling in the later phase confirm that the tape is an approach to maintain an optimal regional immune activation level after soft tissue injury. Overall, the reported electrospun fibrous tape will find its way into clinical transformation and solve the challenges of deep soft tissue injury., (© 2022 Wiley-VCH GmbH.)

Metal ions play a significant role in tissue repair, with widely application in clinical treatment. However, the therapeutic effect of metal ions is always limited due to metabolization and narrow repair capability. Here, a bipolar metal flexible electrospun fibrous membrane based on a metal-organic framework (MOF), which is bioinspired by the gradient structure of the tendon-to-bone interface, with a combination of regulating osteoblasts differentiation and angiogenesis properties, is constructed successfully by a continuous electrospinning technique and matching the longitudinal space morphology for synchronous regeneration. Furthermore, the MOF, acting as carriers, can not only achieve the sustainable release of metal ions, but promote the osteogenesis and tenogenesis on the scaffold. The in vitro data show that this novel hierarchical structure can accelerate the tenogenesis, the biomineralization, and angiogenesis. Moreover, in the in vivo experiment, the flexible fibrous membrane can promote tendon and bone tissue repair, and fibrocartilage reconstruction, to realize the multiple tissue synchronous regeneration at the damaged tendon-to-bone interface. Altogether, this newly developed bipolar metal flexible electrospun fibrous membrane based on a MOF, as a new biomimetic flexible scaffold, has great potential in reconstruct the tissue damage, especially gradient tissue damage., (© 2022 Wiley-VCH GmbH.)

Three dimension (3D) printed scaffolds have been shown to be superior in promoting tissue repair, but the cell-level specific regulatory network activated by 3D printing scaffolds with different material components to form a symbiosis niche have not been systematically revealed. Here, three typical 3D printed scaffolds, including natural polymer hydrogel (gelatin-methacryloyl, GelMA), synthetic polymer material (polycaprolactone, PCL), and bioceramic (β-tricalcium phosphate, β-TCP), are fabricated to explore the regulating effect of the symbiotic microenvironment during bone healing. Enrichment analysis show that hydrogel promotes tissue regeneration and reconstruction by improving blood vessel generation by enhancing oxygen transport and red blood cell development. The PCL scaffold regulates cell proliferation and differentiation by promoting cellular senescence, cell cycle and deoxyribonucleic acid (DNA) replication pathways, accelerating the process of endochondral ossification, and the formation of callus. The β-TCP scaffold can specifically enhance the expression of osteoclast differentiation and extracellular space pathway genes to promote the differentiation of osteoclasts and promote the process of bone remodeling. In these processes, specific biomaterial properties can be used to guide cell behavior and regulate molecular network in the symbiotic microenvironment to reduce the barriers of regeneration and repair., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Inspired by the rapid angiogenesis of natural microvessels in vivo, engineered customizable microvessels (ECMVs) are developed which can naturally angiogenic sprout and induce vascular network formation via combing a celluar coaxial microfluidic extrusion technique with microsurgery post-process. ECMVs can be used for customization of primarily pre-vascularized soft tissue regenerative implants with personalized shape and vascular density with the aid of sacrificial printing technology. After collaborating with surrounding cells, ECMVs angiogenic sprouted and formed daughter vascular networks. Through techniques such as injection and suturing, ECMVs can also be introduced into large bone repair implants for pre-vascularization and osteogenesis promotion. Furthermore, the microvessel networks with personalized shapes are customized by connecting the coaxial microfluidic system to a 3D printer. It is further demonstrated that the vascularization promotion and anastomose with host vessels of the ECMVs in vivo. Thus, ECMVs provide a simple engineering strategy for rapid vascularization of clinically large regenerative soft/hard tissue implants., (© 2021 Wiley-VCH GmbH.)

Three-dimension (3D)-printed bioscaffolds are precise and personalized for bone regeneration. However, customized 3D scaffolds may activate the immune response in vivo and consequently impede bone formation. In this study, with layer-by-layer deposition and electrospinning technology to control the physical structure, 3D-printed PCL scaffolds with PLLA electrospun microfibrous (3D-M-EF) and nanofibrous (3D-N-EF) composites were constructed, and their immunomodulatory effect and the subsequent osteogenic effects were explored. Compared to 3D-N-EF scaffolds, 3D-M-EF scaffolds polarized more RAW264.7 cells toward alternatively activated macrophages (M2), as demonstrated by increased M2 and deceased classically activated macrophage (M1) phenotypic marker expression in the cells. In addition, the 3D-M-EF scaffolds shifted RAW264.7 cells to the M2 phenotype through PI3K/AKT signaling and enhanced VEGF and BMP-2 expression. Conditional medium from the RAW264.7 cells seeded in 3D-M-EF scaffolds promoted osteogenesis of MC3T3-E1 cells. Furthermore, in vivo study of repairing rat calvarial defects, the 3D-M-EF scaffolds increased the polarization of M2 macrophages, enhanced angiogenesis, and accelerated new bone formation. Collectively, our data suggested that well-designed 3D-M-EF scaffolds are favorable for osteogenesis through regulation of M2 polarization. Therefore, it is potential to utilize the physical structure of 3D-printed scaffolds to manipulate the osteoimmune environment to promote bone regeneration., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The ideal bone repair material should firstly recognize and recruit osteoblast precursor cells to initiate the repair process, then promote the differentiation of osteoblasts and accelerate the mineralization of the extracellular matrix (ECM). Here, a bioinspired staged bone regeneration strategy which loads bone morphogenetic protein 2 (BMP 2 )-modified black phosphorus (BP@BMP 2 ) nanosheets to a polylactic acid (PLLA) electrospun fibrous scaffold, with a combination of recruiting osteoblast precursor cells and biomineralization properties for bone regeneration, is constructed successfully by micro-sol electrospinning technique. BP, acting as carriers, can not only provide a negative surface and a strong BMP 2 loading ability but can also promote biomineralization in a 3D manner on the electrospun fibrous scaffold, while the BMP 2 is to target osteoblast precursor cells for recruitment and osteogenesis differentiation, which endows BP@BMP 2 nanosheets with staged bone regeneration ability. Furthermore, the in vitro and in vivo data showed that the BP@BMP 2 loaded electrospun fibrous scaffold have good biocompatibility and a strong osteogenesis ability resulting in rapid new bone tissue regeneration. Altogether, this newly developed bioinspired BMP 2 -modified BP electrospun fiber with staged bone regeneration properties via recruiting osteoblast precursor cells to the bone injured site and accelerating biomineralization can be a promising approach in physiologic bone repair., (© 2020 Wiley-VCH GmbH.)

The strategies concerning modification of the complex immune pathological inflammatory environment during acute spinal cord injury remain oversimplified and superficial. Inspired by the acidic microenvironment at acute injury sites, a functional pH-responsive immunoregulation-assisted neural regeneration strategy was constructed. With the capability of directly responding to the acidic microenvironment at focal areas followed by triggered release of the IL-4 plasmid-loaded liposomes within a few hours to suppress the release of inflammatory cytokines and promote neural differentiation of mesenchymal stem cells in vitro, the microenvironment-responsive immunoregulatory electrospun fibers were implanted into acute spinal cord injury rats. Together with sustained release of nerve growth factor (NGF) achieved by microsol core-shell structure, the immunological fiber scaffolds were revealed to bring significantly shifted immune cells subtype to down-regulate the acute inflammation response, reduce scar tissue formation, promote angiogenesis as well as neural differentiation at the injury site, and enhance functional recovery in vivo. Overall, this strategy provided a delivery system through microenvironment-responsive immunological regulation effect so as to break through the current dilemma from the contradiction between immune response and nerve regeneration, providing an alternative for the treatment of acute spinal cord injury.

Liposome is one of the most commonly used drug delivery systems in the world, due to its excellent biocompatibility, satisfactory ability in controlling drug release, and passive targeting capability. However, some drawbacks limit the application of liposomes in clinical, such as problems in transporting, storing, and difficulties in maintaining the drug concentration in the local area. Scaffolds usually are used as implants to supply certain mechanical supporting to the defective area or utilized as diagnosis and imaging methods. But, in general, unmodified scaffolds show limited abilities in promoting tissue regeneration and treating diseases. Therefore, liposome-scaffold composite systems are designed to take advantages of both liposomes' biocompatibility and scaffolds' strength to provide a novel system that is more suitable for clinical applications. This review introduces and discusses different types of liposomes and scaffolds, and also the application of liposome-scaffold composite systems in different diseases, such as cancer, diabetes, skin-related diseases, infection and human immunodeficiency virus, and in tissue regeneration like bone, teeth, spinal cord and wound healing., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Biomimetic scaffolds have been extensively studied for guiding osteogenesis through structural cues. Inspired by the natural bone growth process, we have employed a hierarchical outer-inner dual reinforcing strategy, which relies on the interfacial ionic bond interaction between amine/calcium and carboxyl groups, to build a nanofiber/particle dual strengthened hierarchical silk fibroin scaffold. This scaffold can provide an applicable form of osteogenic structural cue and mimic the natural bone forming process. Owing to the active interaction between compositions located in the outer pore space and the inner pore wall, the scaffold has over 4 times improvement in the mechanical properties, followed by a significant alteration of the cell-scaffold interaction pattern, demonstrated by over 2 times elevation in the spreading area and enhanced osteogenic activity potentially involving the activities of integrin, vinculin and Yes-associated protein (YAP). The in vivo performance of the scaffold identified the inherent osteogenic effect of the structural cue, which promotes rapid and uniform regeneration. Overall, the hierarchical scaffold is promising in promoting uniform bone regeneration through its specific structural cue endowed by its micro-nano construction.

3D printed scaffolds hold promising perspective for bone tissue regeneration. Inspired by process of bone development stage, 3D printed scaffolds with rapid internal vascularization ability and robust osteoinduction bioactivity will be an ideal bone substitute for clinical use. Here, we fabricated a 3D printed biodegradable scaffold that can control release deferoxamine, via surface aminolysis and layer-by-layer assembly technique, which is essential for angiogenesis and osteogenesis and match to bone development and reconstruction. Our in vitro studies show that the scaffold significantly accelerates the vascular pattern formation of human umbilical endothelial cells, boosts the mineralized matrix production, and the expression of osteogenesis-related genes during osteogenic differentiation of mesenchymal stem cells. In vivo results show that deferoxamine promotes the vascular ingrowth and enhances the bone regeneration at the defect site in a rat large bone defect model. Moreover, this 3D-printed scaffold has excellent biocompatibility that is suitable for mesenchymal stem cells grow and differentiate and possess the appropriate mechanical property that is similar to natural cancellous bone. In summary, this 3D-printed scaffold holds huge potential for clinical translation in the treatment of segmental bone defect, due to its flexibility, economical friendly and practicality., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Developing a highly bioactive bone tissue engineering scaffold that can modulate the bone remodeling process for promoting bone regeneration is a great challenge. In order to tackle this issue, inspired by the balance between bone resorption and formation in the bone remodeling process, here we developed a mesoporous silicate nanoparticle (MSN)-based electrospun polycaprolactone (PCL)/gelatin nanofibrous scaffold to achieve dual delivery of alendronate (ALN) and silicate for a synergetic effect in modulating bone remodeling, where ALN inhibited the bone-resorbing process via preventing guanosine triphosphate-related protein expression, and silicate promoted the bone-forming process via improving vascularization and bone calcification. The scaffold was successfully prepared by encapsulation of ALN into MSNs (ALN@MSNs) and co-electrospinning of an acetic acid-mediated PCL/gelatin homogeneous solution with well-dispersed ALN@MSNs. The results of ALN and Si element release profiles indicated that the ALN@MSN-loaded nanofibers achieved dual release of ALN and silicate (produced due to the hydrolysis of MSNs) simultaneously. The bone repair data from a rat critical-sized cranial defect model revealed that the developed strategy accelerated the healing time from 12 weeks to 4 weeks, almost three times faster, while the other nanofiber groups only had limited bone regeneration at 4 weeks. In addition, we used interactive double-factor analysis of variance for the data of bone volume and maturity to evaluate the synergetic effect of ALN and silicate in promoting bone regeneration, and the result clearly proved our original design and hypothesis. In summary, the presented bone remodeling-inspired electrospun nanofibers with dual delivery of ALN and silicate may be highly promising for bone repair in the clinic.

The incorporation of hydroxyapatite nanoparticles onto the surface of titanium is an effective method to improve its osteoinductive ability. However, there are still issues with the hydroxyapatite nanoparticle coatings fabricated using current methods, such as particle aggregation and unsatisfactory binding ability with the matrix, in addition to the difficulties in the multi-functionalization of antibacterial, anti-wear and bioinductive ability. In the present study, we propose a strategy to fabricate a refined hydroxyapatite nanoparticles/copper nanoparticles co-deposition titanium matrix by the mediation of pulse electrochemical polymerized pyrrole through its coordination and doping of cations and anions. During this process, PO 4 3- in the electrolyte is doped into the corresponding anion structure in the polypyrrole chain and forms HA with Ca 2+ and OH - because of electrostatic interaction. The bioactivity investigation indicates that the composite coatings are able to induce the formation of apatite in supersaturated calcium phosphate solution. Furthermore, the friction and wear tests show that the composite coatings improve the friction properties of the material to a certain extent. The composites also exhibit an antibacterial rate of 97% in the antibacterial test. Finally, in virtue of the dual regulation of polypyrrole by coordination and doping, we successfully fabricate multifunctional hydroxyapatite/copper nano-coatings on titanium surfaces.

Various biomimetic scaffolds with hierarchical micro/nanostructures are designed to closely mimic native extracellular matrix network and to guide cell behavior to promote structural tissue generation. However, it remains a challenge to fabricate hierarchical micro/nanoscaled fibrous scaffolds with different functional components that endow the scaffolds with both biochemical and physical features to exert different biological roles during the process of tissue healing. In this study, a biomimetic designed micro/nanoscaled scaffold with integrated hierarchical dual fibrillar components is fabricated in order to repair dura mater and prevent the formation of epidural scars via collagen molecule self-assembly, electrospinning, and biological interface crosslinking strategies. The fabricated biomimetic scaffolds display micro/nanofibers staggered hierarchical architecture with good mechanical properties and biocompatibility, and it has a more profound effect on attachment, proliferation, and differentiation of fibroblasts. Using a rabbit duraplasty model in vivo, the authors find that dural defects repaired with hierarchical micro/nanoscaled scaffold form a continuous neodura tissue similar to native dura mater; furthermore, the number of scar tissues decreases significantly in the laminectomy sites compared with conventional electrospun microfibrous scaffold. Taken together, these data suggest that the hierarchical micro/nanoscaled fibrous scaffolds with dual fibrillar components may act as a "true" dural substitutes for dual repair., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Development of natural protein-based fibrous scaffolds with tunable physical properties and biocompatibility is highly desirable to construct three-dimensional (3D), fully cellularized scaffolds for wound healing. Herein, we demonstrated a simple and effective technique to construct electrospun 3D fibrous scaffolds for accelerated wound healing using a photocrosslinkable hydrogel based on gelatin methacryloyl (GelMA). We found that the physical properties of the photocrosslinkable hydrogel including water retention, stiffness, strength, elasticity and degradation can be tailored by changing the light exposure time. We further observed that the optimized hydrogel fibrous scaffolds which were soft and elastic could support cell adhesion, proliferation and migration into the whole scaffolds, facilitating regeneration and formation of cutaneous tissues within two weeks. Such tunable characteristics of the fibrous GelMA scaffolds distinguished them from other reported substrates developed for reconstruction of wound defects including glutaraldehyde-crosslinked gelatin or poly (lactic-co-glycolic acid) (PLGA), whose physical and chemical properties were difficult to modify to allow cell infiltration into the 3D scaffolds for tissue regeneration. We anticipate that the ability to become fully cellularized will make the engineered GelMA fibrous scaffolds suitable for widespread applications as skin substitutes or wound dressings., Statement of Significance: In present study, we generate three-dimensional photocrosslinkable gelatin (GelMA)-based fibrous scaffolds with tunable physical and biological properties by using a combined photocrosslinking/electrospinning approach. The developed GelMA fibrous scaffolds can not only support cell viability and cell adhesion, but also facilitate cell migration and proliferation, accelerating regeneration and formation of cutaneous tissues. In addition, the physical properties of the engineered fibrous GelMA hydrogel including water retention capability, mechanical properties and biodegradability can be tuned to accommodate different patients' needs, making it a promising candidate for skin tissue engineering., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Nonhealing chronic wounds on foot are one of the most dreaded complications of diabetes, and biomedical scaffolds remain an attractive option for repairing or regenerating tissues. Accelerating angiogenesis in the early stage after injury is critical to wound healing process; however, the scaffolds accelerate the angiogenesis in the beginning but with the acceleration of vessel network formation the scaffold network hinders the process. In this study, the water soluble drugs-loaded hydrogel nanofibrous scaffolds are designed for rapidly recruiting angiogenesis relative cells and promoting wound healing. The sustained release profile of desferrioxamine (DFO), which continues for about 72 h, leads to significantly increase of neovascularization. The majority of the scaffold is degraded in 14 d, leaving enough space for cell proliferation and vessel formation. The in vitro results show that the scaffolds upregulate the expression of Hif-1α and vascular endothelial growth factor, and enhance the interaction between fibroblasts and endothelial cells. The in vivo studies show a higher expression of angiogenesis related cytokines. This study demonstrates that the DFO released from hydrogel nanofibrous scaffolds of quick degradation can interfere with the required prolyl-hydroxylases cofactors by acting as Fe(2+) chelator and upregulate the expression of Hif-1α, leading to a significant increase of the neovascularization., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Incorporation of bioactive drugs and biofunctionalization of polyester fibrous scaffolds are essential means to improve their bio-functions and histocompatibility for regenerative medicine. However, it is still a challenge to biofunctionalize such drug carriers via traditional biochemical methods while maintaining their properties without changes in drug activity and loading ratio. Here, we demonstrated a facile approach for biofunctionalization of PLGA fibrous scaffolds with various molecules (i.e., PEG polymer, RGD peptide and bFGF growth factor for cell repellent, adhesion and proliferation, respectively) via mussel-Inspired poly(dopamine) (PDA) coating in aqueous solution. By virtue of the mild and efficient nature of this approach, the drug-loaded PLGA fibers could be easily biofunctionalized and showed negligible effects on the scaffold properties, especially drug activity and loading ratio. Further, in vivo study showed that, a ginsenoside-Rg3-loaded fibrous scaffold functionalized with bFGF growth factor could not only promote the early-stage wound healing in rabbit ear wounds (bio-signal from bFGF), but also inhibit later-stage hypertrophic scars formation (release of Rg3 drug). Therefore, the mussel-inspired method for bio-modification provides a facile and effective strategy to combine drug and bio-function in one system, thus facilitating a synergistic effect of drug-therapy and bio-signal when such biomaterial is used for regenerative medicine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Biodegradation-induced inflammation in biodegradable scaffold materials is a critical problem to be addressed due to its potential inducement to tissue necrosis, granulomas, or tumor genesis. Here, a facile strategy for on-demand release of anti-inflammatory drugs and full-course inhibition of degradation-induced inflammation was demonstrated by simply loading an esterase-sensitive prodrug into a fibrous scaffold. In this study, drug release from the prodrug-loaded scaffolds showed an enzyme-triggered release process, which led to an initial moderate release of anti-inflammatory drugs and a later-stage degradation-synchronized drug release. This unique release kinetics ingeniously achieved on-demand drug therapy and efficient inhibition of inflammation throughout the biodegradation in vivo. More importantly, the prodrug-loaded scaffolds prepared with different biodegradable polymers (i.e., different biodegradation rates) all showed drug release kinetics that matched to the biodegradation rates and full-course inhibition of inflammation in vivo. Therefore, this method offered a general approach for on-demand release of anti-inflammatory drugs and efficient inhibition of inflammation throughout the biodegradation of different polymeric scaffolds. In addition, the release kinetics in our system showed potentials for "batch release" of multiple drugs in combination therapies as well as provided a feasible hint for the drug therapies of some other symptoms caused by in vivo biodegradation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Clinically, rotator cuff tear (RCT) is among the most common shoulder pathologies. Despite significant advances in surgical techniques, the re-tear rate after rotator cuff (RC) repair remains high. Insufficient healing capacity is likely the main factor for reconstruction failure. This study reports on a basic fibroblast growth factor (bFGF)-loaded electrospun poly(lactide-co-glycolide) (PLGA) fibrous membrane for repairing RCT. Implantable biodegradable bFGF-PLGA fibrous membranes were successfully fabricated using emulsion electrospinning technology and then characterized and evaluated with in vitro and in vivo cell proliferation assays and repairs of rat chronic RCTs. Emulsion electrospinning fabricated ultrafine fibers with a core-sheath structure which secured the bioactivity of bFGF in a sustained manner for 3 weeks. Histological observations showed that electrospun fibrous membranes have excellent biocompatibility and biodegradability. At 2, 4, and 8 weeks after in vivo RCT repair surgery, electrospun fibrous membranes significantly increased the area of glycosaminoglycan staining at the tendon-bone interface compared with the control group, and bFGF-PLGA significantly improved collagen organization, as measured by birefringence under polarized light at the healing enthesis compared with the control and PLGA groups. Biomechanical testing showed that the electrospun fibrous membrane groups had a greater ultimate load-to-failure and stiffness than the control group at 4 and 8 weeks. The bFGF-PLGA membranes had the highest ultimate load-to-failure, stiffness, and stress of the healing enthesis, and their superiority compared to PLGA alone was significant. These results demonstrated that electrospun fibrous membranes aid in cell attachment and proliferation, as well as accelerating tendon-bone remodeling, and bFGF-loaded PLGA fibrous membranes have a more pronounced effect on tendon-bone healing. Therefore, augmentation using bFGF-PLGA electrospun fibrous membranes is a promising treatment for RCT.

Polymeric nanofibrous composite scaffolds incorporating bioglass and bioceramics have been increasingly promising for bone tissue engineering. In the present study, electrospun poly (l-lactic acid) (PLLA) scaffolds containing dicalcium silicate (C2S) nanoparticles (approximately 300 nm) were fabricated. Using a novel ultrasonic dispersion and aging method, uniform C2S nanoparticles were prepared and they were homogenously distributed in the PLLA nanofibers upon electrospinning. In vitro, the PLLA-C2S fibers induced the formation of HAp on the surface when immersed in simulated body fluid (SBF). During culture, the osteoblastic MC3T3-E1 cells adhered well on PLLA-C2S scaffolds, as evidenced by the well-defined actin stress fibers and well-spreading morphology. Further, compared to pure PLLA scaffolds without C2S, PLLA-C2S scaffolds markedly promoted the proliferation of MC3T3-E1 cells as well as their osteogenic differentiation, which was characterized by the enhanced alkaline phosphatase (ALP) activity. Together, findings from this study clearly demonstrated that PLLA-C2S composite scaffold may function as an ideal candidate for bone tissue engineering., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Skin injury in adult mammals brings about a series of events and inflammation in the wounded area is initiated first and provides lots of inflammatory factors, which is critical for the final scar formation. While the postinjured skin of fetus and nude mice heals scarlessly owing to the absence of inflammation or immunodeficient, we designed a feasible acid-responsive ibuprofen-loaded poly(L-lactide) (PLLA) fibrous scaffolds via doping sodium bicarbonate to prevent excessive inflammation and achieve scarless healing finally. The morphological results of in vivo experiments revealed that animals treated with acid-responsive ibuprofen-loaded PLLA fibrous scaffolds exhibited alleviative inflammation, accelerated healing process, and regulated collagen deposition via interference in the collagen distribution, the α-smooth muscle actin (α-SMA), and the basic fibroblast growth factor (bFGF) expression. The lower ratios of collagen I/collagen III and TGF-β1/TGF-β3 and higher ratio of matrix metalloproteinase-1 (MMP-1)/tissue inhibitor of metalloproteinase-1 (TIMP-1) in acid-responsive ibuprofen-loaded PLLA fibrous scaffolds group were confirmed by real-time qPCR as well. These results suggest that inhibiting the excessive inflammation will result in regular collagen distribution and appropriate ratio between the factors, which promote or suppress the scar formation, then decrease the scar area, and finally achieve the scarless healing.

Clinically, hypertrophic scarring (HS) is a major concern for patients and has been a challenge for surgeons, as there is a lack of treatments that can intervene early in the formation of HS. This study reports on a Chinese drug, 20(R)-ginsenoside Rg3 (GS-Rg3), which can inhibit in vivo the early formation of HS and later HS hyperplasia by inducing the apoptosis of fibroblasts, inhibiting inflammation and down-regulating VEGF expression. Implantable biodegradable GS-Rg3-loaded poly(l-lactide) (PLA) fibrous membranes were successfully fabricated using co-electrospinning technology to control drug release and improve drug utilization. The in vivo releasing time of GS-Rg3 lasts for 3 months, and the drug concentration released in rabbits can be controlled by varying the drug content of the electrospun fibers. Histological observations of HE staining indicate that GS-Rg3/PLA significantly inhibits the HS formation, with obvious improvements in terms of dermis layer thickness, epidermis layer thickness and fibroblast proliferation. The results of immunohistochemistry staining and Masson's trichrome staining demonstrate that GS-Rg3/PLA electrospun fibrous membranes significantly inhibit HS formation, with decreased expression of collagen fibers and microvessels. VEGF protein levels are much lower in the group treated with GS-Rg3/PLA eletrospun membranes compared with other groups. These results demonstrate that GS-Rg3 is a novel drug, capable of inhibiting the early formation of HS and later HS hyperplasia. GS-Rg3/PLA electrospun membrane is a very promising new treatment for early and long-term treatment of HS., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Hypertrophic scarring (HS) has been considered as a great concern for patients and a challenging problem for clinicians as it can be cosmetically disfiguring and functionally debilitating. In this study, Ginsenoside Rg3/Poly(l-lactide) (G-Rg3/PLLA) electrospun fibrous scaffolds covering on the full-thickness skin excisions location was designed to suppress the hypertrophic scar formation in vivo. SEM and XRD results indicated that the crystal G-Rg3 carried in PLLA electrospun fibers was in amorphous state, which facilitates the solubility of G-Rg3 in the PLLA electrospun fibrous scaffolds, and solubility of G-Rg3 in PBS is increased from 3.2 µg/ml for pure G-Rg3 powders to 19.4 µg/ml for incorporated in PLLA-10% fibers. The released G-Rg3 content in the physiological medium could be further altered from 324 to 3445 µg in a 40-day release period by adjusting the G-Rg3 incorporation amount in PLLA electrospun fibers. In vitro results demonstrated that electrospun G-Rg3/PLLA fibrous scaffold could significantly inhibit fibroblast cell growth and proliferation. In vivo results confirmed that the G-Rg3/PLLA electrospun fibrous scaffold showed significant improvements in terms of dermis layer thickness, fibroblast proliferation, collagen fibers and microvessels, revealing that the incorporation of the G-Rg3 in the fibers prevented the HS formation. The above results demonstrate the potential use of G-Rg3/PLLA electrospun fibrous scaffolds to rapidly minimize fibroblast growth and restore the structural and functional properties of wounded skin for patients with deep trauma, severe burn injury, and surgical incision.

Acid-responsive electrospun fibers are fabricated by introducing sodium bicarbonate into PLLA fibers using an emulsion method. This novel electrospun fibrous scaffold exhibits a rapid acid-responsive controlled drug release (early stage) and stable three-dimensional (3D) structure as a tissue engineering scaffold (late stage) for cell growth., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although, electrospun composite fibers have shown promise in enhancing growth, differentiation, and mineralization of osteoblasts in vitro, bone repairing capabilities have not been clarified after in vivo implantation up to now. In situ grown composites (IGC) of hydroxyapatite (HA) and poly(DL-lactide) (PDLLA) were obtained from electrospun fibers grafted with gelatin as the induction sites for HA growth. The presence and location of HA nanoparticles within electrospun fibers were proposed to affect the degradation and repairing process of femoral defects. Subcutaneous implantation of IGC led to around 90% of mass loss and 75% of molecular weight reduction during 16 weeks, which were significantly higher than those after in vitro degradation in buffer solutions. In vitro tests on MC3T3-E1 cells indicated that IGC acted as a better cell support to provide favorable conditions for cell proliferation and to stimulate the osteogenic differentiation as compared with electrospun PDLLA fibers, and blend electrospun fibrous composites. Femoral defects were created for in vivo evaluation of bone repairing, indicating that the entire defect was filled by newly formed bone with compact structure after 16 week implantation of IGC. Histological and SEM observations demonstrated a successful bridging of the critical-sized defect with rapid mineralization, continual remodeling, and abundant vasculature. The in situ grown HA nanoparticles on the surface of electrospun fibers improved the biocompatibility with defect sites, promoted the bone formation within fibrous scaffolds and enhanced the bone remodeling, indicating potentials for bone regeneration and repairing of bone defects., (Copyright © 2012 Wiley Periodicals, Inc.)

Development of natural protein-based fibrous scaffolds with tunable physical properties and biocompatibility is highly desirable to construct three-dimensional (3D), fully cellularized scaffolds for wound healing. Herein, we demonstrated a simple and effective technique to construct electrospun 3D fibrous scaffolds for accelerated wound healing using a photocrosslinkable hydrogel based on gelatin methacryloyl (GelMA). We found that the physical properties of the photocrosslinkable hydrogel including water retention, stiffness, strength, elasticity and degradation can be tailored by changing the light exposure time. We further observed that the optimized hydrogel fibrous scaffolds which were soft and elastic could support cell adhesion, proliferation and migration into the whole scaffolds, facilitating regeneration and formation of cutaneous tissues within two weeks. Such tunable characteristics of the fibrous GelMA scaffolds distinguished them from other reported substrates developed for reconstruction of wound defects including glutaraldehyde-crosslinked gelatin or poly (lactic-co-glycolic acid) (PLGA), whose physical and chemical properties were difficult to modify to allow cell infiltration into the 3D scaffolds for tissue regeneration. We anticipate that the ability to become fully cellularized will make the engineered GelMA fibrous scaffolds suitable for widespread applications as skin substitutes or wound dressings.Statement of significanceIn present study, we generate three-dimensional photocrosslinkable gelatin (GelMA)-based fibrous scaffolds with tunable physical and biological properties by using a combined photocrosslinking/electrospinning approach. The developed GelMA fibrous scaffolds can not only support cell viability and cell adhesion, but also facilitate cell migration and proliferation, accelerating regeneration and formation of cutaneous tissues. In addition, the physical properties of the engineered fibrous GelMA hydrogel including water retention capability, mechanical properties and biodegradability can be tuned to accommodate different patients' needs, making it a promising candidate for skin tissue engineering.

Natural hydrogels are promising scaffolds to engineer epidermis. Currently, natural hydrogels used to support epidermal regeneration are mainly collagen- or gelatin-based, which mimic the natural dermal extracellular matrix but often suffer from insufficient and uncontrollable mechanical and degradation properties. In this study, a photocrosslinkable gelatin (i.e., gelatin methacrylamide (GelMA)) with tunable mechanical, degradation, and biological properties is used to engineer the epidermis for skin tissue engineering applications. The results reveal that the mechanical and degradation properties of the developed hydrogels can be readily modified by varying the hydrogel concentration, with elastic and compressive moduli tuned from a few kPa to a few hundred kPa, and the degradation times varied from a few days to several months. Additionally, hydrogels of all concentrations displayed excellent cell viability (>90%) with increasing cell adhesion and proliferation corresponding to increases in hydrogel concentrations. Furthermore, the hydrogels are found to support keratinocyte growth, differentiation, and stratification into a reconstructed multilayered epidermis with adequate barrier functions. The robust and tunable properties of GelMA hydrogels suggest that the keratinocyte laden hydrogels can be used as epidermal substitutes, wound dressings, or substrates to construct various in vitro skin models.

Highlights: Comprehensive and systematic discussion of vascularized additive manufacturing scaffolds for bone tissue repair is provided. The development mechanism of blood vessels and the relationship between bone tissue engineering and blood vessels are discussed. Vascularized additively manufactured scaffolds in tissue repair are discussed in terms of issues, opportunities, and challenges. Intelligent vascularized 3D/4D/5D/6D-printed tissue scaffolds are discussed. Blood vessels are essential for nutrient and oxygen delivery and waste removal. Scaffold-repairing materials with functional vascular networks are widely used in bone tissue engineering. Additive manufacturing is a manufacturing technology that creates three-dimensional solids by stacking substances layer by layer, mainly including but not limited to 3D printing, but also 4D printing, 5D printing and 6D printing. It can be effectively combined with vascularization to meet the needs of vascularized tissue scaffolds by precisely tuning the mechanical structure and biological properties of smart vascular scaffolds. Herein, the development of neovascularization to vascularization to bone tissue engineering is systematically discussed in terms of the importance of vascularization to the tissue. Additionally, the research progress and future prospects of vascularized 3D printed scaffold materials are highlighted and presented in four categories: functional vascularized 3D printed scaffolds, cell-based vascularized 3D printed scaffolds, vascularized 3D printed scaffolds loaded with specific carriers and bionic vascularized 3D printed scaffolds. Finally, a brief review of vascularized additive manufacturing-tissue scaffolds in related tissues such as the vascular tissue engineering, cardiovascular system, skeletal muscle, soft tissue and a discussion of the challenges and development efforts leading to significant advances in intelligent vascularized tissue regeneration is presented. [ABSTRACT FROM AUTHOR]

Lentiviral‐vector‐based therapies, widely used for treating various diseases, face limitations because of release burst, rapid clearance, and immune activation. Herein, a lentiviral vector delivery platform is proposed utilizing a virus‐engineered microsol electrospun scaffold. Identifying a remarkable upregulation of polypyrimidine tract binding protein1 (PTB) in spinal cord injury (SCI) rats, a scaffold is constructed comprising a hyaluronic acid (HA) core encapsulating brain‐derived neurotrophic factor (BDNF) and a polydopamine (PDA)‐modified linear poly‐l‐lactic acid (PLLA) shell, with shPTB lentiviral vectors (LV‐shPTB) grafted via PDA. In vitro, the LV‐shPTB achieves an infection efficiency of 70%, and the oriented scaffolds significantly reduce the expression of inflammatory factors, induce the reprogramming of fibroblasts into neurons, and sustain the release of BDNF for over 2 weeks. In vivo, the scaffolds provide physical support and neural guidance, as well as released BDNF and LV‐shPTB. LV‐shPTB delivery leads to the reprogramming of fibroblasts into neurons, and the sustained BDNF delivery maintains the neurons' proliferation and growth, which further promotes the recovery of neurological function in SCI rats. These results demonstrate the potential application of virus‐engineered delivery platforms in SCI treatment and other medical fields. [ABSTRACT FROM AUTHOR]

The differentiation potentials and viability of stem cells are often impaired during cell isolation and delivery. Inspired by the phenomenon where islands can recruit seabirds for nesting, "cell island" microgels (MGs), that is, growth factor‐loaded methacrylated hyaluronic acid and heparin blend MGs, which can recruit endogenous stem cells and promote chondrogenic differentiation, are constructed using microfluidic technology and photopolymerization processes, followed by non‐covalently binding platelet‐derived growth factor‐BB (PDGF‐BB) and transforming growth factor‐beta3 (TGF‐β3). The loading efficiency of PDGF‐BB and TGF‐β3 are 96% and 91%, respectively. In vitro and in vivo experiments find that the "cell island" MGs can enhance the migratory capacity of cells and recruit them from their niche via releasing PDGF‐BB. Meanwhile, by using hyaluronic acid, the "cell island" MGs provide a suitable microenvironment for cell attachment and spreading. Furthermore, the "cell island" MGs induce chondrogenic differentiation of the recruited cells via releasing TGF‐β3 and present a promising therapeutic effect for osteoarthritis. In sum, this developed "cell island" MG might serve as a temporary "nest site" to allow the migration, adhesion, and differentiation of endogenous stem cells, which can be a promising candidate rather than the conventional cell‐seeded scaffolds for promoting tissue regeneration. [ABSTRACT FROM AUTHOR]

The development of science and technology often drew lessons from natural phenomena. Herein, inspired by drying‐driven curling of apple peels, hydrogel‐based micro‐scaled hollow tubules (MHTs) are proposed for biomimicking microvessels, which promote microcirculation and improve the survival of random skin flaps. MHTs with various pipeline structures are fabricated using hydrogel in corresponding shapes, such as Y‐branches, anastomosis rings, and triangle loops. Adjustable diameters can be achieved by altering the concentration and cross‐linking time of the hydrogel. Based on this rationale, biomimetic microvessels with diameters of 50–500 µm are cultivated in vitro by coculture of MHTs and human umbilical vein endothelial cells. In vivo studies show their excellent performance to promote microcirculation and improve the survival of random skin flaps. In conclusion, the present work proposes and validifies a biomimetic 3D self‐forming method for the fabrication of biomimetic vessels and microvascular scaffolds with high biocompatibility and stability based on hydrogel materials, such as gelatin and hyaluronic acid. [ABSTRACT FROM AUTHOR]

Distal necrosis of random skin flap is always clinical problematic in plastic surgery. The development of 3D functional vascular networks is fundamental for the survival of a local random skin flap. Herein, an effective technique on constructing 3D fibrous scaffolds for accelerated vascularization is demonstrated using a photocrosslinkable natural hydrogel based on gelatin methacryloyl (GelMA) by electrospinning. It is found that the ultraviolet (UV) photocrosslinkable gelatin electrospun hydrogel fibrous membranes exhibit soft adjustable mechanical properties and controllable degradation properties. Furthermore, it is observed that the optimized hydrogel scaffolds can support endothelial cells and dermal fibroblasts adhesion, proliferation, and migration into the scaffolds, which facilitates vascularization. Importantly, a rapid formation of tubes is observed after 3 d seeding of endothelial cells. After GelMA fibrous scaffold implantation below the skin flap in a rat model, it is found that the flap survival rate is higher than the control group, and there is more microvascular formation, which is potentially beneficial for the flap tissue vascularization. These data suggest that GelMA hydrogels can be used for biomedical applications that require the formation of microvascular networks, including the development of complex engineered tissues. [ABSTRACT FROM AUTHOR]

• Capillarity of scaffolds could absorb and retain EPSCs immediately post-surgery. • MMP-responsive release of drug promoted recruitment and chondrogenesis of ESPCs. • In vivo cartilage defects were repaired in situ by the enzyme-responsive scaffolds. A capillarity-functional and enzyme-responsive porous scaffold was developed to not only absorb and retain ESPCs from bone marrow blood rapidly via capillarity at the early stage after implantation, but also regulate the chemotactic recruitment and chondrogenic differentiation of ESPCs in response to the local inflammatory microenvironment. We researched the mechanism and effect of capillarity in scaffolds, as well as the enzyme-responsive release of PEGKGN to realize function division. Importantly, a rat cartilage defect model was built to verify the in situ cartilage regeneration through the capillarity-functional and enzyme-responsive porous scaffolds. [Display omitted] In situ cartilage regeneration with endogenous stem/progenitor cells (ESPCs) and bioactive scaffolds is attractive in cartilage regeneration. Nevertheless, the optimization of ESPCs recruitment and the establishment of chondrogenic microenvironment are still a huge challenge for better therapeutic outcomes. Herein, a in situ cartilage tissue engineering porous scaffold with enzyme-responsive kartogenin (KGN) release is prepared to not only recruit ESPCs via chemoattractant, but also promote their chondrogenesis. Polyethylene glycol-modified Kartogenin (PEGKGN) and polycaprolactone (PCL) are grafted on poly(L-glutamic acid) (PLGA) to endow the porous scaffolds with good mechanical property, capillarity and enzyme-responsiveness. The scaffolds show a fast absorption of protein solution through capillarity, indicating its capacity of rapid fill with bone marrow blood at the early stage after implantation for the maximum absorption and retention of ESPCs. The release dose of PEGKGN is found to be accelerated by matrix metalloproteinase-2 (MMP-2). And the high-dose PEGKGN can stimulate the migration of bone marrow mesenchyml stem cells (BMSCs) obviously, and the low-dose PEGKGN can promote the chondrogenesis of BMSCs in vitro. The in vivo data demonstrates that the bioactive porous scaffolds enhance in situ cartilage regeneration. The neo-tissues show close structures and components to the healthy cartilages. Thus, the in situ cartilage tissue engineering porous scaffolds with enzyme-responsive KGN release can recruit ESPCs to defects and promote the chondrogenesis effectively, which is a potential treatment for in situ cartilage regeneration. [ABSTRACT FROM AUTHOR]

Sodium deoxycholate is used to decellularize porcine dermis and obtain ATM with low immunogenicity. The ATM and human-derived Bp are mixed in different volume ratios to prepare a highly active biomacromolecule scaffold with osteoinductive and osteoconductive activities in a simulated bone healing microenvironment. A rat cranial defect model was used to evaluate the effects of different scaffolds on bone regeneration. [Display omitted] • Sodium deoxycholate decellularizes porcine dermis to obtain acellular tissue matrix (ATM) with low immunogenicity. • ATM combines with different contents of human bone powder (Bp). • Highly active biomacromolecule three-dimensional scaffold with osteoinductive and osteoconductive properties. • Bp/ATM perfectly simulate the natural osteogenesis microenvironment. • The 50 %Bp/ATM scaffold promotes bone regeneration in rat cranial defects. Regenerative medicine for bone tissue in the oral cavity aims to repair alveolar or jaw defects. An ideal, highly active, osteoinductive, three-dimensional scaffold that can effectively promote cell proliferation and differentiation has not been reported. This study evaluated the in vitro and in vivo efficacy of a biological macromolecule composite scaffold derived from porcine dermal matrix bone tissue decellularized using sodium deoxycholate technology. The composite scaffold was composed of a porcine dermal acellular tissue matrix and human bone powder. The bone powder/acellular tissue matrix (Bp/ATM) scaffold was porous with a porosity exceeding 70%. Bp/ATM provided an osteoinductive scaffold that recruited osteoblasts to the site of injury and promoted their differentiation to bone cells. The 50% (v/v) bone-scaffold mixture significantly accelerated mineralized matrix production and the expression of osteogenesis-related proteins during osteogenic differentiation in vitro. This mixture also enhanced bone regeneration at the defect site in vivo in a rat cranial defect model. These observations suggest that Bp/ATM forms a highly active osteoinductive and osteoconductive scaffold that is a promising biomaterial for bone regeneration. [ABSTRACT FROM AUTHOR]