PI3K/AKT/mTOR signaling regulates BCP ceramic-induced osteogenesis.

An increasing number of studies demonstrate that biphasic calcium phosphate (BCP) ceramics can induce bone regeneration. However, the underlying molecular mechanisms involved are still poorly understood. This work was proposed to investigate how PI3K/AKT/mTOR signaling influenced the osteogenesis mediated by BCP ceramics. The results showed that incubation with BCP ceramics promoted the proliferation of murine bone marrow-derived mesenchymal stem cells (BMSCs) in a time-dependent manner. The resulting cell proliferation was then suppressed by the selective inhibition of either PI3K, AKT, or mTOR signaling activation. Next, we confirmed that BCP ceramics up-regulated the phosphorylation levels of AKT and mTOR in BMSCs, suggesting the ability of BCP ceramics to drive the activation of PI3K/AKT/mTOR signaling in BMSCs. Furthermore, the blockade of PI3K/AKT/mTOR signaling prevented BCP ceramics-induced osteogenic differentiation and pro-angiogenesis of BMSCs by down-regulating the expression of genes encoding OPN, RUNX2 or VEGF. Moreover, the PI3K/AKT/mTOR signaling blockade suppressed stem cell infiltration and new bone formation in the implants following intra-muscular implantation of BCP ceramics in mice. Therefore, our results suggested that PI3K/AKT/mTOR signaling played a critical regulatory role in BCP ceramic-induced osteogenesis.

Collagen-based hydrogels induce stem cell chondrogenesis and hyaline cartilage regeneration: an in vivo study.

Injectable, self-crosslinking collagen-based hydrogels are beneficial for chondrocytes to secrete matrix, positioning them as promising candidates for cartilage tissue engineering. However, previous studies lacked insight into the ability of cell-free collagen-based hydrogels to regenerate hyaline cartilage defect. Therefore, this study aimed to evaluate the potential of collagen-based hydrogels (Col and ColHA) to induce chondrogenic differentiation of stem cells and in situ hyaline cartilage regeneration. Both Col and ColHA hydrogels self-crosslinked in situ and exhibited similar physical properties. In vitro experiments showed they supported the survival, adhesion, spreading, and proliferation of bone marrow stem cells (BMSCs). Moreover, both hydrogels induced ectopic differentiation of BMSCs into chondrocytes when implanted subcutaneously into the back of nude mice. ColHA hydrogel notably enhanced type II collagen secretion. The results of repairing cartilage defects in situ revealed both hydrogels facilitated hyaline cartilage regeneration and maintained cartilage phenotype without exogenous BMSCs. Hydrogels encapsulating BMSCs expedited cartilage repair, and ColHA/BMSC constructs showed better mechanical properties, suggesting their potential for cartilage repair applications. This study implies that collagen-based hydrogels are good candidates for hyaline cartilage regeneration.

A 3D printable near-infrared triggered hydrogel with MoS2 as the crosslink center for tissue repair.

Near-infrared (NIR) light, compared with ultraviolet (UV) light, has a stronger tissue penetration ability and is widely used in the medical field. However, few hydrogels can be triggered by NIR. Here, a modular polymer-nanosheet (metal disulfide) (PNS) hydrogel system was proposed, which can be photo-crosslinked through photothermal conversion under NIR light. MoS2, a transition-metal dichalcogenide, was used as a crosslink center in PNS hydrogels. Mo and S (from thiolated polymers), which are essential for gelation, were discovered to have new bonds. Furthermore, 3D printing of NIR-triggered PNS hydrogels was achieved conceptually with masked NIR. Moreover, multiple hydrogels and metal disulfides were applicable in this modular gelation system. This study indicated that these PNS hydrogels have great potential in many smart biomedical applications, including wearable sensors, noninvasive in vivo 3D bioprinting, and tissue repair substitutes.

3D printing calcium phosphate ceramics with high osteoinductivity through pore architecture optimization.

The osteoinductivity of 3D printed calcium phosphate (CaP) ceramics has a large gap compared with those prepared by conventional foaming methods, and improving the osteoinductivity of 3D printing CaP ceramics is crucial for successful application in bone regeneration. Pore architecture plays a critical role in osteoinductivity. In this study, CaP ceramics with a hexagonal close-packed (HCP) spherical pore structure were successfully fabricated using DLP printing technology. Additionally, octahedral (Octahedral), diamond (Diamond), and helical (Gyroid) structures were constructed with similar porosity and macropore diameter. CaP ceramics with the HCP structure exhibited higher compression strength (8.39 ± 1.82 MPa) and lower permeability (6.41 × 10-11 m2) compared to the Octahedral, Diamond, and Gyroid structures. In vitro cellular responses indicated that the macropore architecture strongly influenced the local growth rate of osteoblast-formed cell tissue; cells grew uniformly and formed circular rings in the HCP group. Furthermore, the HCP group promoted the expression of osteogenic genes and proteins more effectively than the other three groups. The outstanding osteoinductivity of the HCP group was confirmed in canine intramuscular implantation studies, where the new bone area reached up to 8.02 ± 1.94 % after a 10-week implantation. Additionally, the HCP group showed effective bone regeneration in repairing femoral condyle defects. Therefore, our findings suggest that 3D printed CaP bioceramics with an HCP structure promote osteoinductivity and can be considered as candidates for personalized precise treatment of bone defects in clinical applications. STATEMENT OF SIGNIFICANCE: 1. 3D printing BCP ceramics with high osteoinductivity were constructed through pore architecture optimization. 2. BCP ceramics with HCP structure exhibited relatively higher mechanical strength and lower permeability than those with Octahedral, Diamond and Gyroid structures. 3. BCP ceramics with HCP structure could promote the osteogenic differentiation of MC3T3-E1, and showed the superior in-vivo osteoinductivity and bone regeneration comparing with the other structures.

3D Printed Calcium Phosphate Physiochemically Dual-Regulating Pro-Osteogenesis and Antiosteolysis for Enhancing Bone Tissue Regeneration.

Osteoblasts and osteoclasts are two of the most important types of cells in bone repair, and their bone-forming and bone-resorbing activities influence the process of bone repair. In this study, we proposed a physicochemical bidirectional regulation strategy via ration by physically utilizing hydroxyapatite nanopatterning to recruit and induce MSCs osteogenic differentiation and by chemically inhibiting osteolysis activity through the loaded zoledronate. The nanorod-like hydroxyapatite coating was fabricated via a modified hydrothermal process while the zoledronic acid was loaded through the chelation within the calcium ions. The fabrication of a hydroxyapatite/zoledronic acid composite biomaterial. This biomaterial promotes bone tissue regeneration by physically utilizing hydroxyapatite nanopatterning to recruit and induce MSCs osteogenic differentiation and by chemically inhibiting osteolysis activity through the loaded zoledronate. The nanorod-like hydroxyapatite coating was fabricated via a modified hydrothermal process while the zoledronic acid was loaded through the chelation within the calcium ions. The in vitro results tested on MSCs and RAW 246.7 indicated that the hydroxyapatite enhanced cells' physical sensing system, therefore enhancing the osteogenesis. At the same time the zoledronic acid inhibited osteolysis by downregulating the RANK-related genes. This research provides a promising strategy for enhancing bone regeneration and contributes to the field of orthopedic implants.

Design and performance of double-layered artificial chordae.

Surgical repair with artificial chordae replacement has emerged as a standard treatment for mitral regurgitation. Expanded polytetrafluoroethylene (ePTFE) sutures are commonly employed as artificial chordae; however, they have certain limitations, such as potential long-term rupture and undesired material/tissue response. This study introduces a novel approach to artificial chordae design, termed the New Artificial Chordae (NAC), which incorporates a double-layered structure. The NAC comprises a multi-strand braided core composed of ultra-high molecular weight polyethylene (UHMWPE) fibers as the inner core, and an outer tube made of hydrophobic porous ePTFE. Compared to traditional ePTFE sutures, NAC exhibits increased flexibility, enhanced tensile strength, longer elongation and improved fatigue resistance. Moreover, NAC exhibits a more hydrophobic surface, which contributes to enhanced hemocompatibility. The study also includes in vivo investigations conducted on animal models to evaluate the biocompatibility and functional efficacy of the artificial chordae. These experiments demonstrate the enhanced durability and biocompatibility of the NAC, characterized by improved mechanical strength, minimal tissue response and reduced thrombus formation. These findings suggest the potential application of NAC as a prosthetic chordae replacement, offering promising prospects to address the limitations associated with current artificial chordae materials and providing novel ideas and approaches for the development of sustainable and biocompatible regenerative biomaterials.

Nanosilicate-reinforced GelMA-PEGDA hydrogel promotes angiogenesis for bone regeneration.

Bone tissue engineering has emerged as a pivotal field addressing the critical clinical needs of bone fractures. This study focused on developing multi-composite hydrogels by synergizing biocompatible GelMA macromolecules with synthetic PEGDA and reinforcing them with nanosilicates (SN). The incorporation of SN introduces crucial trace elements such as silicon, magnesium, and lithium, promoting both angiogenesis and osteogenesis. Characterizations revealed that PEGDA significantly reinforced the composite hydrogels' stability, while SN further enhanced the mechanical integrity of the GelMA-PEGDA-SN (GPS) hydrogels. Cell studies designated that GPS improved cell proliferation and migration, angiogenic VEGF/eNOS expression and osteogenic differentiation. In vivo experiments showed that GPS hydrogels effectively enhanced calvarial bone healing, with the GPS-2 formulation (2 % SN) displaying superior bone coverage and increased vascular formation. Assessments of osteogenic formation and the angiogenic marker CD31 validated the comprehensive bone regeneration potential of GPS hydrogels. These findings highlight the significant promise of GPS hydrogels in fostering bone healing with promoted angiogenesis.

Hyaluronated nanohydroxyapatite responsively released from injectable hydrogels for targeted therapy of melanoma.

Nanohydroxyapatite (nHAp) has attracted significant attention for its tumor suppression and tumor microenvironment modulation capabilities. However, a strong tendency to aggregate greatly affects its anti-tumor efficiency. To address this issue, a hydrogel platform consisting of thiolated hyaluronic acid (HA-SH) modified nanohydroxyapatite (nHAp-HA) and HA-SH was developed for sustained delivery of nHAp for melanoma therapy. The hydrophilic and negatively charged HA-SH significantly improved the size dispersion and stability of nHAp in aqueous media while conferring nHAp targeting effects. Covalent sulfhydryl self-cross-linking between HA-SH and nHAp-HA groups ensured homogeneous dispersion of nHAp in the matrix material. Meanwhile, the modification of HA-SH conferred the targeting properties of nHAp and enhanced cellular uptake through the HA/CD44 receptor. The hydrogel platform could effectively reduce the aggregation of nHAp and release nHAp in a sustained and orderly manner. Antitumor experiments showed that the modified nHAp-HA retained the tumor cytotoxicity of nHAp in vitro and inhibited the growth of highly malignant melanomas up to 78.6% while being able to induce the differentiation of macrophages to the M1 pro-inflammatory and antitumor phenotype. This study will broaden the application of nanohydroxyapatite in tumor therapy.

A robust and biodegradable hydroxyapatite/poly(lactide-co-ε-caprolactone) electrospun membrane for dura repair.

Typically occurring after trauma or neurosurgery treatments, dura mater defect and the ensuing cerebrospinal fluid (CSF) leakage could lead to a number of serious complications and even patient's death. Although numerous natural and synthetic dura mater substitutes have been reported, none of them have been able to fulfill the essential properties, such as anti-adhesion, leakage blockage, and pro-dura rebuilding. In this study, we devised and prepared a series of robust and biodegradable hydroxyapatite/poly(lactide-co-ε-caprolactone) (nHA/PLCL) membranes for dura repair via an electrospinning technique. In particular, PLLA/PCL (80/20) was selected for electrospinning due to its mechanical properties that most closely resembled natural dural tissue. Studies by SEM, XRD, water contact angle and in vitro degradation showed that the introduction of nHA would destroy PLCL's crystalline structure, which would further affect the mechanical properties of the nHA/PLCL membranes. When the amount of nHA added increased, so did the wettability and in vitro degradation rate, which accelerated the release of nHA. In addition, the high biocompatibility of nHA/PLCL membranes was demonstrated by in vitro cytotoxicity data. The in vivo rabbit dura repair model results showed that nHA/PLCL membranes provided a strong physical barrier to stop tissue adhesion at dura defects. Meanwhile, the nHA/PLCL and commercial group's CSF had a significantly lower number of inflammatory cells than the control groups, validating the nHA/PLCL's ability to effectively lower the risk of intracranial infection. Findings from H&E and Masson-trichrome staining verified that the nHA/PLCL electrospun membrane was more favorable for fostering dural defect repair and skull regeneration. Moreover, the relative molecular weight of PLCL declined dramatically after 3 months of implantation, according to the results of the in vivo degradation test, but it retained the fiber network structure and promoted tissue growth, demonstrating the good stability of the nHA/PLCL membranes. Collectively, the nHA/PLCL electrospun membrane presents itself as a viable option for dura repair.

Microenvironment-responsive release of Mg2+ from tannic acid decorated and multilevel crosslinked hydrogels accelerates infected wound healing.

The management of chronic infected wounds poses significant challenges due to frequent bacterial infections, high concentrations of reactive oxygen species, abnormal immune regulation, and impaired angiogenesis. This study introduces a novel, microenvironment-responsive, dual dynamic, and covalently bonded hydrogel, termed OHA-P-TA/G/Mg2+. It is derived from the reaction of tannic acid (TA) with phenylboronic acids (PBA), which are grafted onto oxidized hyaluronic acid (OHA-P-TA), combined with GelMA (G) via a Schiff base and chemical bonds, along with the incorporation of Mg2+. This hydrogel exhibits pH and ROS dual-responsiveness, demonstrating effective antibacterial capacity, antioxidant ability, and the anti-inflammatory ability under distinct acidic and oxidative microenvironments. Furthermore, the release of Mg2+ from the TA-Mg2+ network (TA@Mg2+) promotes the transformation of pro-inflammatory M1 phenotype macrophages to anti-inflammatory M2 phenotype, showing a microenvironment-responsive response. Finally, in vivo results indicate that the OHA-P-TA/G/Mg2+ hydrogel enhances epithelial regeneration, collagen deposition, and neovascularization, showing great potential as an effective dressing for infected wound repair.

Porous gradient hydrogel promotes skin regeneration by angiogenesis.

The skin has a multilayered structure, and deep-seated injuries are exposed to external microbial invasion and in vivo microenvironmental destabilization. Here, a bilayer bionic skin scaffold (Bilayer SF) was developed based on methacrylated sericin protein to mimic the skin's multilayered structure and corresponding functions. The outer layer (SF@TA), which mimics the epidermal layer, was endowed with the function of resisting external bacterial and microbial invasion using a small pore structure and bio-crosslinking with tannic acid (TA). The inner layer (SF@DA@Gel), which mimics the dermal layer, was used to promote cellular growth using a large pore structure and introducing dopamine (DA) to regulate the wound microenvironment. This Bilayer SF showed good mechanical properties and structural stability, satisfactory antioxidant and promote cell proliferation and migration abilities. In vitro studies confirmed the antimicrobial properties of the outer layer and the pro-angiogenic ability of the inner layer. In vivo animal studies demonstrated that the bilayer scaffolds promoted collagen deposition, neovascularization, and marginal hair follicle formation, which might be a promising new bionic skin scaffold.

Development of a multifunctional nano-hydroxyapatite platform (nHEA) for advanced treatment of severely infected full-thickness skin wounds.

The treatment of full-thickness skin injuries complicated by severe infection is hampered by the lack of comprehensive solutions that can regulate the various stages of wound healing. Consequently, there is an urgent need for a multifunctional dressing capable of multi-level regulation. In this study, we propose a novel solution by covalently integrating ε-poly-l-lysine-grafted gallic acid (EG) and in situ bioreduced silver nanoparticles (AgNPs) onto nano-hydroxyapatite (nHAP), thereby developing a multi-layered, multifunctional nanoplatform (nHEA). Cell experiments have shown that, compared to nHAP and nHAP loaded only with EG (nHEG), the addition of AgNPs to nHEA confers excellent antibacterial properties while maintaining optimal biocompatibility. The incorporation of EG onto nHEG and nHEA imparts antioxidation, anti-inflammatory, and pro-angiogenic functions, and the release of Ca2+ and EG further enhances fibroblast migration and collagen secretion. In a rat model of full-thickness skin injury with severe infection, nHEA demonstrates remarkable antibacterial and anti-inflammatory effects, along with promoting collagen remodeling and regeneration. Together, both cell experiments and animal studies confirm the significant potential of this innovative multifunctional nanoplatform in the treatment of full-thickness skin injuries with severe infection. STATEMENT OF SIGNIFICANCE: Treating infected full-thickness skin injuries poses a longstanding challenge due to the lack of comprehensive solutions that can regulate different stages of wound healing. This study introduces a novel multifunctional nanoplatform, nHEA, developed by covalently integrating ε-poly-l-lysine grafted with gallic acid (EG) and in situ bioreduced AgNPs onto nano-hydroxyapatite (nHAP). Cell experiments reveal that the integration of AgNPs enhances nHEA's antibacterial performance while maintaining optimal biocompatibility. The inclusion of EG bestows antioxidant, inflammation-regulating, and angiogenetic properties upon nHEA, and the release of Ca2+ and EG stimulates the migration and collagen secretion of fibroblast cells. Consequently, nHEA exhibits superior antibacterial and inflammation-regulating efficacy, and stimulates collagen remodeling and regeneration in vivo, making it a promising treatment for severely infected skin injuries.

Osteo-immunomodulatory effects of macrophage-derived extracellular vesicles treated with biphasic calcium phosphate ceramics on bone regeneration.

Literature on osteoimmunology has demonstrated that macrophages have a great influence on biomaterial-induced bone formation. However, there are almost no reports clarifying the osteo-immunomodulatory capacity of macrophage-derived extracellular vesicles (EVs). This study comprehensively investigated the effects of EVs derived from macrophages treated with biphasic calcium phosphate (BCP) ceramics (BEVs) on vital events associated with BCP-induced bone formation such as immune response, angiogenesis, and osteogenesis. It was found that compared with EVs derived from macrophages alone (control, CEVs), BEVs preferentially promoted macrophage polarization towards a wound-healing M2 phenotype, enhanced migration, angiogenic differentiation, and tube formation of human umbilical vein endothelial cells, and induced osteogenic differentiation of mesenchymal stem cells. Analysis of 15 differentially expressed microRNAs (DEMs) related to immune, angiogenesis, and osteogenesis suggested that BEVs exhibited good immunomodulatory, pro-angiogenic, and pro-osteogenic abilities, which might be attributed to their specific miRNA cargos. These findings not only deepen our understanding of biomaterial-mediated osteoinduction, but also suggest that EVs derived from biomaterial-treated macrophages hold great promise as therapeutic agents with desired immunomodulatory capacity for bone regeneration.

A Redox-Triggered Autophagy-Induced Nanoplatform with PD-L1 Inhibition for Enhancing Combined Chemo-Immunotherapy.

Epirubicin (EPI) alone can trigger mildly protective autophagy in residual tumor cells, resulting in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and leads to antiprogrammed death ligand 1 (anti-PD-1)/PD-L1 therapy resistance, posing a significant clinical challenge in tumor immunotherapy. The combination of checkpoint inhibitors targeting the PD-1/PD-L1 pathway and amplifying autophagy presents an innovative approach to tumor treatment, which can prevent tumor immune escape and enhance therapeutic recognition. Herein, we aimed to synthesize a redox-triggered autophagy-induced nanoplatform with SA&EA-induced PD-L1 inhibition. The hyaluronic acid (HA) skeleton and arginine segment promoted active nanoplatform targeting, cell uptake, and penetration. The PLGLAG peptide was cleaved by overexpressing matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, and the PD-L1 inhibitor D-PPA was released to inhibit tumor immune escape. The intense autophagy inducers, STF-62247 and EPI, were released owing to the cleavage of disulfide bonds influenced by the high glutathione (GSH) concentration in tumor cells. The combination of EPI and STF induced apoptosis and autophagic cell death, effectively eliminating a majority of tumor cells. This indicated that the SA&EA nanoplatform has better therapeutic efficacy than the single STF@AHMPP and EPI@AHMPTP groups. This research provided a way to set up a redox-triggered autophagy-induced nanoplatform with PD-L1 inhibition to enhance chemo-immunotherapy.

Nano-hydroxyapatite promotes cell apoptosis by co-activating endoplasmic reticulum stress and mitochondria damage to inhibit glioma growth.

Despite a growing body of studies demonstrating the specific anti-tumor effect of nano-hydroxyapatite (n-HA), the underlying mechanism remained unclear. Endoplasmic reticulum (ER) and mitochondria are two key players in intracellular Ca2+ homeostasis and both require Ca2+ to participate. Moreover, the ER-mitochondria interplay coordinates the maintenance of cellular Ca2+ homeostasis to prevent any negative consequences from excess of Ca2+, hence there needs in-depth study of n-HA effect on them. In this study, we fabricated needle-like n-HA to investigate the anti-tumor effectiveness as well as the underlying mechanisms from cellular and molecular perspectives. Data from in vitro experiments indicated that the growth and invasion of glioma cells were obviously reduced with the aid of n-HA. It is interesting to note that the expression of ER stress biomarkers (GRP78, p-IRE1, p-PERK, PERK, and ATF6) were all upregulated after n-HA treatment, along with the activation of the pro-apoptotic transcription factor CHOP, showing that ER stress produced by n-HA triggered cell apoptosis. Moreover, the increased expression level of intracellular reactive oxygen species and the mitochondrial membrane depolarization, as well as the downstream cell apoptotic signaling activation, further demonstrated the pro-apoptotic roles of n-HA induced Ca2+ overload through inducing mitochondria damage. The in vivo data provided additional evidence that n-HA caused ER stress and mitochondria damage in cells and effectively restrain the growth of glioma tumors. Collectively, the work showed that n-HA co-activated intracellular ER stress and mitochondria damage are critical triggers for cancer cells apoptosis, offering fresh perspectives on ER-mitochondria targeted anti-tumor therapy.

Structure driven bio-responsive ability of injectable nanocomposite hydrogels for efficient bone regeneration.

Injectable hydrogels are promising for treatment of bone defects in clinic owing to their minimally invasive procedure. Currently, there is limited emphasis on how to utilize injectable hydrogels to mobilize body's regenerative potential for enhancing bone regeneration. Herein, an injectable bone-mimicking hydrogel (BMH) scaffold assembled from nanocomposite microgel building blocks was developed, in which a highly interconnected microporous structure and an inorganic/organic (methacrylated hydroxyapatite and methacrylated gelatin) interweaved nano structure were well-designed. Compared with hydrogels lacking micro-nano structures or only showing microporous structure, the BMH scaffold enhanced the ingrowth of vessels and promoted the formation of dense cellular networks (including stem cells and M2 macrophages), across the entire scaffold at early stage after subcutaneous implantation. Moreover, the BMH scaffold could not only directly trigger osteogenic differentiation of the infiltrated stem cells, but also provided an instructive osteo-immune microenvironment by inducing macrophages into M2 phenotype. Mechanistically, our results reveal that the nano-rough structure of the BMH plays an essential role in inducing macrophage M2 polarization through activating mechanotransduction related RhoA/ROCK2 pathway. Overall, this work offers an injectable hydrogel with micro-nano structure driven bio-responsive abilities, highlighting harnessing body's inherent regenerative potential to realize bone regeneration.

3D printing of customized bioceramics for promoting bone tissue regeneration by regulating sympathetic nerve behavior.

Numerous studies have shown that there are multiple neural activities involved in the process of bone resorption and bone regeneration, and promoting osteogenesis by promoting neural network reconstruction is an effective strategy for repairing critical size bone defects. However, traumatic bone defects often cause activation of the sympathetic nervous system (SNS) in the damaged area, releasing excess catecholamines (CAs), resulting in a decrease in the rate of bone formation. Herein, a 3D-printed scaffold loaded with propranolol (PRN) is proposed to reduce CA concentrations in bone defect areas and promote bone regeneration through drug release. For this purpose, PRN-loaded methacrylated gelatin (GelMA) microspheres were mixed with low-concentration GelMA and perfused into a 3D-printed porous hydroxyapatite (HAp) scaffold. By releasing PRN, which can block ß-adrenergic receptors, it hinders the activation of sympathetic nerves and inhibits the release of excess CA by the SNS. At the same time, the composite scaffold recruits bone marrow mesenchymal stem cells (BMSCs) and promotes the differentiation of BMSCs in the direction of osteoblasts, which effectively promotes bone regeneration in the rabbit femoral condyle defect model. The results of the study showed that the release of PRN from the composite scaffold could effectively hinder the activation of sympathetic nerves and promote bone regeneration, providing a new strategy for the treatment of bone defects.

Advancements in Photothermal Therapy Using Near-Infrared Light for Bone Tumors.

Bone tumors, particularly osteosarcoma, are prevalent among children and adolescents. This ailment has emerged as the second most frequent cause of cancer-related mortality in adolescents. Conventional treatment methods comprise extensive surgical resection, radiotherapy, and chemotherapy. Consequently, the management of bone tumors and bone regeneration poses significant clinical challenges. Photothermal tumor therapy has attracted considerable attention owing to its minimal invasiveness and high selectivity. However, key challenges have limited its widespread clinical use. Enhancing the tumor specificity of photosensitizers through targeting or localized activation holds potential for better outcomes with fewer adverse effects. Combinations with chemotherapies or immunotherapies also present avenues for improvement. In this review, we provide an overview of the most recent strategies aimed at overcoming the limitations of photothermal therapy (PTT), along with current research directions in the context of bone tumors, including (1) target strategies, (2) photothermal therapy combined with multiple therapies (immunotherapies, chemotherapies, and chemodynamic therapies, magnetic, and photodynamic therapies), and (3) bifunctional scaffolds for photothermal therapy and bone regeneration. We delve into the pros and cons of these combination methods and explore current research focal points. Lastly, we address the challenges and prospects of photothermal combination therapy.

An injectable cartilage-coating composite with long-term protection, effective lubrication and chondrocyte nourishment for osteoarthritis treatment.

The osteoarthritic (OA) environment within articular cartilage poses significant challenges, resulting in chondrocyte dysfunction and cartilage matrix degradation. While intra-articular injections of anti-inflammatory drugs, biomaterials, or bioactive agents have demonstrated some effectiveness, they primarily provide temporary relief from OA pain without arresting OA progression. This study presents an injectable cartilage-coating composite, comprising hyaluronic acid and decellularized cartilage matrix integrated with specific linker polymers. It enhances the material retention, protection, and lubrication on the cartilage surface, thereby providing an effective physical barrier against inflammatory factors and reducing the friction and shear force associated with OA joint movement. Moreover, the composite gradually releases nutrients, nourishing OA chondrocytes, aiding in the recovery of cellular function, promoting cartilage-specific matrix production, and mitigating OA progression in a rat model. Overall, this injectable cartilage-coating composite offers promising potential as an effective cell-free treatment for OA. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) in the articular cartilage leads to chondrocyte dysfunction and cartilage matrix degradation. This study introduces an intra-articular injectable composite material (HDC), composed of decellularized cartilage matrix (dECMs), hyaluronan (HA), and specially designed linker polymers to provide an effective cell-free OA treatment. The linker polymers bind HA and dECMs to form an integrated HDC structure with an enhanced degradation rate, potentially reducing the need for frequent injections and associated trauma. They also enable HDC to specifically coat the cartilage surface, forming a protective and lubricating layer that enhances long-term retention, acts as a barrier against inflammatory factors, and reduces joint movement friction. Furthermore, HDC nourishes OA chondrocytes through gradual nutrient release, aiding cellular function recovery, promoting cartilage-specific matrix production, and mitigating OA progression.

Engineered Microchannel Scaffolds with Instructive Niches Reinforce Endogenous Bone Regeneration by Regulating CSF-1/CSF-1R Pathway.

Structural and physiological cues provide guidance for the directional migration and spatial organization of endogenous cells. Here, a microchannel scaffold with instructive niches is developed using a circumferential freeze-casting technique with an alkaline salting-out strategy. Thereinto, polydopamine-coated nano-hydroxyapatite is employed as a functional inorganic linker to participate in the entanglement and crystallization of chitosan molecules. This scaffold orchestrates the advantage of an oriented porous structure for rapid cell infiltration and satisfactory immunomodulatory capacity to promote stem cell recruitment, retention, and subsequent osteogenic differentiation. Transcriptomic analysis as well as its in vitro and in vivo verification demonstrates that essential colony-stimulating factor-1 (CSF-1) factor is induced by this scaffold, and effectively bound to the target colony-stimulating factor-1 receptor (CSF-1R) on the macrophage surface to activate the M2 phenotype, achieving substantial endogenous bone regeneration. This strategy provides a simple and efficient approach for engineering inducible bone regenerative biomaterials.