Oxygen-Releasing Hyaluronic Acid-Based Dispersion with Controlled Oxygen Delivery for Enhanced Periodontal Tissue Engineering.

Periodontitis is a chronic biofilm-associated inflammatory disease of the tooth-supporting tissues that causes tooth loss. It is strongly associated with anaerobic bacterial colonization and represents a substantial global health burden. Due to a local hypoxic environment, tissue regeneration is impaired. Oxygen therapy has shown promising results as a potential treatment of periodontitis, but so far, local oxygen delivery remains a key technical challenge. An oxygen (O2)-releasing hyaluronic acid (HA)-based dispersion with a controlled oxygen delivery was developed. Cell viability of primary human fibroblasts, osteoblasts, and HUVECs was demonstrated, and biocompatibility was tested using a chorioallantoic membrane assay (CAM assay). Suppression of anaerobic growth of Porphyromonas gingivalis was shown using the broth microdilution assay. In vitro assays showed that the O2-releasing HA was not cytotoxic towards human primary fibroblasts, osteoblasts, and HUVECs. In vivo, angiogenesis was enhanced in a CAM assay, although not to a statistically significant degree. Growth of P. gingivalis was inhibited by CaO2 concentrations higher than 256 mg/L. Taken together, the results of this study demonstrate the biocompatibility and selective antimicrobial activity against P. gingivalis for the developed O2-releasing HA-based dispersion and the potential of O2-releasing biomaterials for periodontal tissue regeneration.

Early Reciprocal Effects in a Murine Model of Traumatic Brain Injury and Femoral Fracture.

Traumatic brain injury (TBI) represents a major cause of death and disability in early adulthood. Concomitant extracranial injury such as long bone fracture was reported to exacerbate TBI pathology. However, early reciprocal effects and mechanisms have been barely investigated. To address this issue, C57BL/6N mice were subjected to either the controlled cortical impact (CCI) model of TBI, fracture of the left femur (FF), combined injury (CCI+FF), or sham procedure. Behavioral alterations were monitored until 5 days post injury (dpi), followed by (immuno-)histology, gene and protein expression analyses using quantitative PCR, western blot, and ELISA. We found that CCI+FF mice exhibited increased neurological impairments, reduced recovery, and altered anxiety-related behavior compared to single injury groups. At 5 dpi, cerebral lesion size was not affected by combined injury but exaggerated hippocampal substance loss and increased perilesional astrogliosis were observed in CCI+FF mice compared to isolated CCI. Bone gene expression of the osteogenic markers Runx2, osteocalcin, alkaline phosphatase, and bone sialoprotein was induced by fracture injury but attenuated by concomitant TBI. Plasma concentrations of the biomarkers osteopontin and progranulin were elevated in CCI+FF mice compared to other experimental groups. Taken together, using a murine model of TBI and femoral fracture, we report early reciprocal impairments of brain tissue maintenance, behavioral recovery, and bone repair gene expression. Increased circulating levels of the biomarkers osteopontin and progranulin indicate ongoing tissue inflammation and repair. Our results may have implications for future therapeutic approaches to interfere with the pathological crosstalk between TBI and concomitant bone fracture.

Dexamethasone Inhibits the Pro-Angiogenic Potential of Primary Human Myoblasts.

Tissue regeneration depends on the complex processes of angiogenesis, inflammation and wound healing. Regarding muscle tissue, glucocorticoids (GCs) inhibit pro-inflammatory signalling and angiogenesis and lead to muscle atrophy. Our hypothesis is that the synthetic GC dexamethasone (dex) impairs angiogenesis leading to muscle atrophy or inhibited muscle regeneration. Therefore, this study aims to elucidate the effect of dexamethasone on HUVECs under different conditions in mono- and co-culture with myoblasts to evaluate growth behavior and dex impact with regard to muscle atrophy and muscle regeneration. Viability assays, qPCR, immunofluorescence as well as ELISAs were performed on HUVECs, and human primary myoblasts seeded under different culture conditions. Our results show that dex had a higher impact on the tube formation when HUVECs were maintained with VEGF. Gene expression was not influenced by dex and was independent of cells growing in a 2D or 3D matrix. In co-culture CD31 expression was suppressed after incubation with dex and gene expression analysis revealed that dex enhanced expression of myogenic transcription factors, but repressed angiogenic factors. Moreover, dex inhibited the VEGF mediated pro angiogenic effect of myoblasts and inhibited expression of angiogenic inducers in the co-culture model. This is the first study describing a co-culture of human primary myoblast and HUVECs maintained under different conditions. Our results indicate that dex affects angiogenesis via inhibition of VEGF release at least in myoblasts, which could be responsible not only for the development of muscle atrophy after dex administration, but also for inhibition of muscle regeneration after vascular damage.

Progress of Phototherapy Applications in the Treatment of Bone Cancer.

Bone cancer including primary bone cancer and metastatic bone cancer, remains a challenge claiming millions of lives and affecting the life quality of survivors. Conventional treatments of bone cancer include wide surgical resection, radiotherapy, and chemotherapy. However, some bone cancer cells may remain or recur in the local area after resection, some are highly resistant to chemotherapy, and some are insensitive to radiotherapy. Phototherapy (PT) including photodynamic therapy (PDT) and photothermal therapy (PTT), is a clinically approved, minimally invasive, and highly selective treatment, and has been widely reported for cancer therapy. Under the irradiation of light of a specific wavelength, the photosensitizer (PS) in PDT can cause the increase of intracellular ROS and the photothermal agent (PTA) in PTT can induce photothermal conversion, leading to the tumoricidal effects. In this review, the progress of PT applications in the treatment of bone cancer has been outlined and summarized, and some envisioned challenges and future perspectives have been mentioned. This review provides the current state of the art regarding PDT and PTT in bone cancer and inspiration for future studies on PT.

Detecting the Effects of the Glucocorticoid Dexamethasone on Primary Human Skeletal Muscle Cells-Differences to the Murine Cell Line.

Skeletal muscle atrophy is characterized by a decrease in muscle fiber size as a result of a decreased protein synthesis, which leads to degradation of contractile muscle fibers. It can occur after denervation and immobilization, and glucocorticoids (GCs) may also increase protein breakdown contributing to the loss of muscle mass and myofibrillar proteins. GCs are already used in vitro to induce atrophic conditions, but until now no studies with primary human skeletal muscle existed. Therefore, this study deals with the effects of the GC dexamethasone (dex) on primary human myoblasts and myotubes. After incubation with 1, 10, and 100 µM dex for 48 and 72 h, gene and protein expression analyses were performed by qPCR and Western blot. Foxo, MuRF-1, and MAFbx were significantly upregulated by dex, and there was increased gene expression of myogenic markers. However, prolonged incubation periods demonstrated no Myosin protein degradation, but an increase of MuRF-1 expression. In conclusion, applying dex did not only differently affect primary human myoblasts and myotubes, as differences were also observed when compared to murine cells. Based on our findings, studies using cell lines or animal cells should be interpreted with caution as signaling transduction and functional behavior might differ in diverse species.

Rose Bengal Crosslinking to Stabilize Collagen Sheets and Generate Modulated Collagen Laminates.

For medical application, easily accessible biomaterials with tailored properties are desirable. Collagen type I represents a biomaterial of choice for regenerative medicine and tissue engineering. Here, we present a simple method to modify the properties of collagen and to generate collagen laminates. We selected three commercially available collagen sheets with different thicknesses and densities and examined the effect of rose bengal and green light collagen crosslinking (RGX) on properties such as microstructure, swelling degree, mechanical stability, cell compatibility and drug release. The highest impact of RGX was measured for Atelocollagen, for which the swelling degree was reduced from 630% (w/w) to 520% (w/w) and thickness measured under force application increased from 0.014 mm to 0.455 mm, indicating a significant increase in mechanical stability. Microstructural analysis revealed that the sponge-like structure was replaced by a fibrous structure. While the initial burst effect during vancomycin release was not influenced by crosslinking, RGX increased cell proliferation on sheets of Atelocollagen and on Collagen Solutions. We furthermore demonstrate that RGX can be used to covalently attach different sheets to create materials with combined properties, making the modification and combination of readily available sheets with RGX an attractive approach for clinical application.

Intramuscular Injection of Combined Calf Blood Compound (CFC) and Homeopathic Drug Tr14 Accelerates Muscle Regeneration In Vivo.

Skeletal muscle injuries in competitive sports cause lengthy absences of athletes from tournaments. This is of tremendous competitive and economic relevance for both the athletes and their respective clubs. Therapy for structural muscle lesions aims to promote regeneration and fast-track return-to-play. A common clinical treatment strategy for muscle injuries is the intramuscular injection of calf blood compound and the homeopathic drug, Tr14. Although the combination of these two agents was reported to reduce recovery time, the regulatory mechanism whereby this occurs remains unknown. In this in vivo study, we selected a rat model of mechanical muscle injury to investigate the effect of this combination therapy on muscle regeneration. Gene expression analysis and histological images revealed that this combined intramuscular injection for muscle lesions can enhance the expression of pro-myogenic genes and proteins and accelerate muscle regeneration. These findings are novel and depict the positive effects of calf blood compound and the homeopathic drug, Tr14, which are utilized in the field of Sports medicine.

Biofabrication of SDF-1 Functionalized 3D-Printed Cell-Free Scaffolds for Bone Tissue Regeneration.

Large segmental bone defects occurring after trauma, bone tumors, infections or revision surgeries are a challenge for surgeons. The aim of our study was to develop a new biomaterial utilizing simple and cheap 3D-printing techniques. A porous polylactide (PLA) cylinder was printed and functionalized with stromal-derived factor 1 (SDF-1) or bone morphogenetic protein 7 (BMP-7) immobilized in collagen type I. Biomechanical testing proved biomechanical stability and the scaffolds were implanted into a 6 mm critical size defect in rat femur. Bone growth was observed via x-ray and after 8 weeks, bone regeneration was analyzed with µCT and histological staining methods. Development of non-unions was detected in the control group with no implant. Implantation of PLA cylinder alone resulted in a slight but not significant osteoconductive effect, which was more pronounced in the group where the PLA cylinder was loaded with collagen type I. Addition of SDF-1 resulted in an osteoinductive effect, with stronger new bone formation. BMP-7 treatment showed the most distinct effect on bone regeneration. However, histological analyses revealed that newly formed bone in the BMP-7 group displayed a holey structure. Our results confirm the osteoinductive character of this 3D-biofabricated cell-free new biomaterial and raise new options for its application in bone tissue regeneration.

Calf Blood Compound (CFC) and Homeopathic Drug Induce Differentiation of Primary Human Skeletal Muscle Cells.

The use of injections to treat structural muscle injuries is controversially discussed. In our controlled in vitro study, we investigated the biological impact of Actovegin and Traumeel alone and in combination on primary human skeletal muscle cells. Cells were characterized by immunofluorescence staining for myogenic factor 5 (Myf5) and MyoD, and cultured with or without Actovegin and / or Traumeel. The effects of these agents were assayed by cell viability and gene expression of the specific markers MyoD, Myf5, neural adhesion molecule (NCAM), and CD31. Myotube formation was determined by myosin staining. Neither Actovegin nor Traumeel showed toxic effects or influenced cell viability significantly. High volumes of Actovegin down-regulated gene expression of NCAM after 3 days but had no effect on MyoD, Myf5, and CD31 gene expression. High volumes of Traumeel inhibited MyoD gene expression after 3 days, whereas after 7 days MyoD expression was significantly up-regulated. The combination of both agents did not significantly influence cell viability or gene expression. This is the first study demonstrating that Actovegin and Traumeel potentially modulate human skeletal muscle cells. The relevance of these in vitro findings has to be highlighted in further in vivo studies.

A New Bone Substitute Developed from 3D-Prints of Polylactide (PLA) Loaded with Collagen I: An In Vitro Study.

Although a lot of research has been performed, large segmental bone defects caused by trauma, infection, bone tumors or revision surgeries still represent big challenges for trauma surgeons. New and innovative bone substitutes are needed. Three-dimensional (3D) printing is a novel procedure to create 3D porous scaffolds that can be used for bone tissue engineering. In the present study, solid discs as well as porous cage-like 3D prints made of polylactide (PLA) are coated or filled with collagen, respectively, and tested for biocompatibility and endotoxin contamination. Microscopic analyses as well as proliferation assays were performed using various cell types on PLA discs. Stromal-derived factor (SDF-1) release from cages filled with collagen was analyzed and the effect on endothelial cells tested. This study confirms the biocompatibility of PLA and demonstrates an endotoxin contamination clearly below the FDA (Food and Drug Administration) limit. Cells of various cell types (osteoblasts, osteoblast-like cells, fibroblasts and endothelial cells) grow, spread and proliferate on PLA-printed discs. PLA cages loaded with SDF-1 collagen display a steady SDF-1 release, support cell growth of endothelial cells and induce neo-vessel formation. These results demonstrate the potential for PLA scaffolds printed with an inexpensive desktop printer in medical applications, for example, in bone tissue engineering.

Reduced fibroblast adhesion and proliferation on plasma-modified titanium surfaces.

Soft tissue complications are clinically relevant problems after osteosynthesis of fractures. The goal is to develop a method for reduction of fibroblast adhesion and proliferation on titanium implant surfaces by plasma polymerisation of the organo-silicon monomer hexamethyldisiloxane (HMDSO). HMDSO was deposited under continuous wave conditions in excess oxygen (ppHMDSO surface) and selected samples were further modified with an additional oxygen plasma (ppHMDSO + O2 surface). Surface characterization was performed by scanning electron microscopy, profilometry, water contact angle measurements, infrared reflection absorption spectroscopy and X-ray photoelectron spectroscopy. In our experimental setup the mechanical properties, roughness and topography of the titanium were preserved, while surface chemistry was drastically changed. Fibroblast proliferation was assessed by alamarBlue assay, cell morphology by confocal microscopy visualization of eGFP-transducted fibroblasts, and cell viability by Annexine V/propidium iodide assay. Both modified surfaces, non-activated hydrophobic ppHMDSO and activated hydrophilic ppHMDSO + O2 were able to dramatically reduce fibroblast colonization and proliferation compared to standard titanium. However, this effect was more strongly pronounced on the hydrophobic ppHMDSO surface, which caused reduced cell adhesion and prevented proliferation of fibroblasts. The results demonstrate that plasma modifications of titanium using HMDSO are valuable candidates for future developments in anti-adhesive and anti-proliferative coatings for titanium fracture implants.

Animal models for acquired heterotopic ossification.

Heterotopic ossification (HO), the ectopic formation of bone in soft tissues, is a relevant musculoskeletal disorder that, by reduction of range of motion, may lead to significant impairment of quality of live. HO can either be acquired or hereditary. Acquired HO is seen most often after hip prosthetic surgery and pelvic trauma. In contrast, hereditary HO is commonly observed in the axial skeleton, but can affect every joint. Substantial effort has been directed towards understanding the pathophysiology and towards finding both, effective prophylactic and therapeutic treatments. Every improvement of the understanding of the pathophysiologic changes underlying HO as well as the rationale of prophylactic and therapeutic treatment regimens in the end, is based on the study of appropriate animal models. Although intriguing models of 'genetic' HO have been developed recently, their relevance to acquired HO remains questionable. As there is still neither proper treatment nor reliable prophylaxis, animal models will remain important in the study of HO. Currently, there are 6 different animal models regularly used for the study of acquired HO. Some of these models can reflect a merely particular part of the disease. Hence, selection of the appropriate animal model for the study of HO is exceedingly important. The present paper reviews the history and major features of the different animal models of acquired HO, and reveals some of the insights gained through the study of animal models; important biochemical and pathophysiological key features are highlighted. Clinical studies have proved indometacine, celecoxib and radiation therapy to be effective in reducing the occurrence of HO, but not always be able to prevent it.

Brain-Bone Crosstalk in a Murine Polytrauma Model Promotes Bone Remodeling but Impairs Neuromotor Recovery and Anxiety-Related Behavior.

Traumatic brain injury (TBI) and long bone fractures are a common injury pattern in polytrauma patients and modulate each other's healing process. As only a limited number of studies have investigated both traumatic sites, we tested the hypothesis that brain-bone polytrauma mutually impacts neuro- and osteopathological outcomes. Adult female C57BL/6N mice were subjected to controlled cortical impact (CCI), and/or osteosynthetic stabilized femoral fracture (FF), or sham surgery. Neuromotor and behavioral impairments were assessed by neurological severity score, open field test, rotarod test, and elevated plus maze test. Brain and bone tissues were processed 42 days after trauma. CCI+FF polytrauma mice had increased bone formation as compared to FF mice and increased mRNA expression of bone sialoprotein (BSP). Bone fractures did not aggravate neuropathology or neuroinflammation assessed by cerebral lesion size, hippocampal integrity, astrocyte and microglia activation, and gene expression. Behavioral assessments demonstrated an overall impaired recovery of neuromotor function and persistent abnormalities in anxiety-related behavior in polytrauma mice. This study shows enhanced bone healing, impaired neuromotor recovery and anxiety-like behavior in a brain-bone polytrauma model. However, bone fractures did not aggravate TBI-evoked neuropathology, suggesting the existence of outcome-relevant mechanisms independent of the extent of brain structural damage and neuroinflammation.

Integrated design and application of stimuli-responsive metal-organic frameworks in biomedicine: current status and future perspectives.

In recent years, metal-organic frameworks (MOFs) have garnered widespread attention due to their distinctive attributes, such as high surface area, tunable properties, biodegradability, extremely low density, high loading capacity, diverse chemical functionalities, thermal stability, well-defined pore sizes, and molecular dimensions. Increasingly, biomedical researchers have turned their focus towards their multifaceted development. Among these, stimuli-responsive MOFs, with their unique advantages, have captured greater interest from researchers. This review will delve into the merits and drawbacks of both endogenous and exogenous stimuli-responsive MOFs, along with their application directions. Furthermore, it will outline the characteristics of different synthesis routes of MOFs, exploring various design schemes and modification strategies and their impacts on the properties of MOF products, as well as how to control them. Additionally, we will survey different types of stimuli-responsive MOFs, discussing the significance of various MOF products reported in biomedical applications. We will categorically summarize different strategies such as anticancer therapy, antibacterial treatment, tissue repair, and biomedical imaging, as well as insights into the development of novel MOFs nanomaterials in the future. Finally, this review will conclude by summarizing the challenges in the development of stimuli-responsive MOFs in the field of biomedicine and providing prospects for future research endeavors.

Metal-organic framework-based advanced therapeutic tools for antimicrobial applications.

The escalating concern over conventional antibiotic resistance has emphasized the urgency in developing innovative antimicrobial agents. In recent times, metal-organic frameworks (MOFs) have garnered significant attention within the realm of antimicrobial research due to their multifaceted antimicrobial attributes, including the sustained release of intrinsic or exogenous antimicrobial components, chemodynamically catalyzed generation of reactive oxygen species (ROS), and formation of photogenerated ROS. This comprehensive review provides a thorough overview of the synthetic approaches employed in the production of MOF-based materials, elucidating their underlying antimicrobial mechanisms in depth. The focal point lies in elucidating the research advancements across various antimicrobial modalities, encompassing intrinsic component release system, extraneous component release system, auto-catalytical system, and energy conversion system. Additionally, the progress of MOF-based antimicrobial materials in addressing wound infections, osteomyelitis, and periodontitis is meticulously elucidated, culminating in a summary of the challenges and potential opportunities inherent within the realm of antimicrobial applications for MOF-based materials. STATEMENT OF SIGNIFICANCE: Growing concerns about conventional antibiotic resistance emphasized the need for alternative antimicrobial solutions. Metal-organic frameworks (MOFs) have gained significant attention in antimicrobial research due to their diverse attributes like sustained antimicrobial components release, catalytic generation of reactive oxygen species (ROS), and photogenerated ROS. This review covers MOF synthesis and their antimicrobial mechanisms. It explores advancements in intrinsic and extraneous component release, auto-catalysis, and energy conversion systems. The paper also discusses MOF-based materials' progress in addressing wound infections, osteomyelitis, and periodontitis, along with existing challenges and opportunities. Given the lack of related reviews, our findings hold promise for future MOF applications in antibacterial research, making it relevant to your journal's readership.

Recent advances in metal-organic frameworks for stimuli-responsive drug delivery.

After entering the human body, drugs for treating diseases, which are prone to delivery and release in an uncontrolled manner, are affected by various factors. Based on this, many researchers utilize various microenvironmental changes encountered during drug delivery to trigger drug release and have proposed stimuli-responsive drug delivery systems. In recent years, metal-organic frameworks (MOFs) have become promising stimuli-responsive agents to release the loaded therapeutic agents at the target site to achieve more precise drug delivery due to their high drug loading, excellent biocompatibility, and high stimuli-responsiveness. The MOF-based stimuli-responsive systems can respond to various stimuli under pathological conditions at the site of the lesion, releasing the loaded therapeutic agent in a controlled manner, and improving the accuracy and safety of drug delivery. Due to the changes in different physical and chemical factors in the pathological process of diseases, the construction of stimuli-responsive systems based on MOFs has become a new direction in drug delivery and controlled release. Based on the background of the rapidly increasing attention to MOFs applied in drug delivery, we aim to review various MOF-based stimuli-responsive drug delivery systems and their response mechanisms to various stimuli. In addition, the current challenges and future perspectives of MOF-based stimuli-responsive drug delivery systems are also discussed in this review.

A review of biomacromolecule-based 3D bioprinting strategies for structure-function integrated repair of skin tissues.

When skin is damaged or affected by diseases, it often undergoes irreversible scar formation, leading to aesthetic concerns and psychological distress for patients. In cases of extensive skin defects, the patient's life can be severely compromised. In recent years, 3D printing technology has emerged as a groundbreaking approach to skin tissue engineering, offering promising solutions to various skin-related conditions. 3D bioprinting technology enables the precise fabrication of structures by programming the spatial arrangement of cells within the skin tissue and subsequently printing skin replacements either in a 3D bioprinter or directly at the site of the defect. This study provides a comprehensive overview of various biopolymer-based inks, with a particular emphasis on chitosan (CS), starch, alginate, agarose, cellulose, and fibronectin, all of which are natural polymers belonging to the category of biomacromolecules. Additionally, it summarizes artificially synthesized polymers capable of enhancing the performance of these biomacromolecule-based bioinks, thereby composing hybrid biopolymer inks aimed at better application in skin tissue engineering endeavors. This review paper examines the recent advancements, characteristics, benefits, and limitations of biological 3D bioprinting techniques for skin tissue engineering. By utilizing bioinks containing seed cells, hydrogels with bioactive factors, and biomaterials, complex structures resembling natural skin can be accurately fabricated in a layer-by-layer manner. The importance of biological scaffolds in promoting skin wound healing and the role of 3D bioprinting in skin tissue regeneration processes is discussed. Additionally, this paper addresses the challenges and constraints associated with current 3D bioprinting technologies for skin tissue and presents future perspectives. These include advancements in bioink formulations, full-thickness skin bioprinting, vascularization strategies, and skin appendages bioprinting.

Towards optimized tissue regeneration: a new 3D printable bioink of alginate/cellulose hydrogel loaded with thrombocyte concentrate.

Introduction: Autologous platelet concentrate (APC) are pro-angiogenic and can promote wound healing and tissue repair, also in combination with other biomaterials. However, challenging defect situations remain demanding. 3D bioprinting of an APC based bioink encapsulated in a hydrogel could overcome this limitation with enhanced physio-mechanical interface, growth factor retention/secretion and defect-personalized shape to ultimately enhance regeneration. Methods: This study used extrusion-based bioprinting to create a novel bioink of alginate/cellulose hydrogel loaded with thrombocyte concentrate. Chemico-physical testing exhibited an amorphous structure characterized by high shape fidelity. Cytotoxicity assay and incubation of human osteogenic sarcoma cells (SaOs2) exposed excellent biocompatibility. enzyme-linked immunosorbent assay analysis confirmed pro-angiogenic growth factor release of the printed constructs, and co-incubation with HUVECS displayed proper cell viability and proliferation. Chorioallantoic membrane (CAM) assay explored the pro-angiogenic potential of the prints in vivo. Detailed proteome and secretome analysis revealed a substantial amount and homologous presence of pro-angiogenic proteins in the 3D construct. Results: This study demonstrated a 3D bioprinting approach to fabricate a novel bioink of alginate/cellulose hydrogel loaded with thrombocyte concentrate with high shape fidelity, biocompatibility, and substantial pro-angiogenic properties. Conclusion: This approach may be suitable for challenging physiological and anatomical defect situations when translated into clinical use.

Integrated osteoimmunomodulatory strategies based on designing scaffold surface properties in bone regeneration.

Those who have used traditional biomaterials as bone substitutes have always regarded the immune response as an obstacle leading to implant failure. However, cumulative evidence revealed that blindly minimizing host immune reactions cannot induce successful bone regeneration. With the emergence of the new concept of osteoimmunology, the intimate mutual effects between the skeletal system and the immune system have been gradually recognized, promoting the innovation of biomaterials with osteoimmunomodulatory properties. By tuning the surface properties, biomaterials can precisely manipulate the osteoimmune environment favoring bone regeneration. In this review, we first reviewed the mutual effects between the skeletal system and the immune system to show the importance of immunomodulation on bone regeneration. Subsequently, we summarize the recent developments in surface modification strategies in terms of the surface physicochemical properties and surface coatings and explain how these modification strategies work.

Design and fabrication of intracellular therapeutic cargo delivery systems based on nanomaterials: current status and future perspectives.

Intracellular cargo delivery, the introduction of small molecules, proteins, and nucleic acids into a specific targeted site in a biological system, is an important strategy for deciphering cell function, directing cell fate, and reprogramming cell behavior. With the advancement of nanotechnology, many researchers use nanoparticles (NPs) to break through biological barriers to achieving efficient targeted delivery in biological systems, bringing a new way to realize efficient targeted drug delivery in biological systems. With a similar size to many biomolecules, NPs possess excellent physical and chemical properties and a certain targeting ability after functional modification on the surface of NPs. Currently, intracellular cargo delivery based on NPs has emerged as an important strategy for genome editing regimens and cell therapy. Although researchers can successfully deliver NPs into biological systems, many of them are delivered very inefficiently and are not specifically targeted. Hence, the development of efficient, target-capable, and safe nanoscale drug delivery systems to deliver therapeutic substances to cells or organs is a major challenge today. In this review, on the basis of describing the research overview and classification of NPs, we focused on the current research status of intracellular cargo delivery based on NPs in biological systems, and discuss the current problems and challenges in the delivery process of NPs in biological systems.