Stimulate Bone Regeneration Research Articles

Effects of ethanol pretreatment on osteogenic activity and off-flavors in blue mussel (Mytilus edulis L.) enzymatic hydrolysates

Aquatic protein hydrolysates have many biological activities, but the off-flavor seriously decreases their commercial acceptability. Therefore, it is important to invest in finding an effective deodorization of aquatic hydrolysates that do not affect activities. In this study, ethanol pretreatment of mussel was applied to establish a new method to deodorize the blue mussel (Mytilus edulis L.) hydrolysates. LC-MS and GC–MS analysis results showed that 87.34% of fatty acids, 83.94% of aldehydes, most volatile flavor compounds including aldehydes, ketones, alcohols, acids, and hydrocarbons were decreased after ethanol pretreatment. Besides, it was found that the enzymatic hydrolysates of mussel with or without ethanol pretreatment showed high osteogenic activity, which induced an increase of 33.65 ± 4.36% and 31.77 ± 5.45% in MC3T3-E1 cell growth. These results suggest that ethanol pretreatment has beneficial potential for improving the flavor aspects of blue mussel peptides which may have the potential to stimulate bone regeneration and formation.

A Computational Model for the Release of Bioactive Molecules by the Hydrolytic Degradation of a Functionalized Polyester-Based Scaffold.

This work presents a computational model to study the degradation behavior of polyester-based three-dimensional (3D) functionalized scaffolds for bone regeneration. As a case study, we investigated the behavior of a 3D-printed scaffold presenting a functionalized surface with ICOS-Fc, a bioactive protein able to stimulate bone regeneration and healing, inhibiting osteoclast activity. The aim of the model was to optimize the scaffold design to control its degradation and thus the release of grafted protein over time and space. Two different scenarios were considered: (i) a scaffold without macroporosity presenting a functionalized external surface; and (ii) a scaffold presenting an internal functionalized macroporous architecture with open channels to locally deliver the degradation products.

Recent Developments in Polymer Nanocomposites for Bone Regeneration.

Most people who suffer acute injuries in accidents have fractured bones. Many of the basic processes that take place during embryonic skeletal development are replicated throughout the regeneration process that occurs during this time. Bruises and bone fractures, for example, serve as excellent examples. It almost always results in a successful recovery and restoration of the structural integrity and strength of the broken bone. After a fracture, the body begins to regenerate bone. Bone formation is a complex physiological process that requires meticulous planning and execution. A normal healing procedure for a fracture might reveal how the bone is constantly rebuilding as an adult. Bone regeneration is becoming more dependent on polymer nanocomposites, which are composites made up of a polymer matrix and a nanomaterial. This study will review polymer nanocomposites that are employed in bone regeneration to stimulate bone regeneration. As a result, we will introduce the role of bone regeneration nanocomposite scaffolds, and the nanocomposite ceramics and biomaterials that play a role in bone regeneration. Aside from that, recent advances in polymer nanocomposites might be used in a variety of industrial processes to help people with bone defects overcome their challenges will be discussed.

Novel Biomaterial-Binding/Osteogenic Bi-Functional Peptide Binds to Silk Fibroin Membranes to Effectively Induce Osteogenesis In Vitro and In Vivo.

Peptides can introduce new functions to biomaterials but their immobilization usually relies on inefficient physical adsorption or tedious chemical conjugation. Using the Bombyx mori silk fibroin (SF) membrane (SFm) as a model biomaterial, here, we demonstrate a universal strategy for discovering new peptides that can "stick" to a biomaterial to functionalize it. Specifically, two peptide motifs, one screened by phage display biopanning for binding to the biomaterial (i.e., SF) and another derived from an osteogenic growth factor (i.e., bone morphogenetic protein-2), are fused into a new chimeric peptide that can bind to SFm for more efficient osteogenesis. Theoretical simulations and experimental assays confirm that the chimeric peptide binds to SF with high affinity, facilely achieving its immobilization onto SFm. The peptide enables SFm to effectively induce osteogenic differentiation of human mesenchymal stem cells (MSCs) even without other osteogenic inducers and efficiently stimulate bone regeneration in a subcutaneous rat model in 8 weeks, even without MSC seeding, while not causing inflammatory responses. Since biomaterial-binding peptides can be readily screened using phage display and functional peptides can be generated from growth factors, our work suggests a universal strategy for combining them to seek new peptides for binding and functionalizing biomaterials.

Combined Application of BMP-2 and Naturally Occurring Bioactive Factor Mixtures for the Optimized Therapy of Segmental Bone Defects.

Critical bone defects are the result of traumatic, infection- or tumor-induced segmental bone loss and represent a therapeutic problem that has not been solved by current reconstructive or regenerative strategies yet. Scaffolds functionalized with naturally occurring bioactive factor mixtures show a promising chemotactic and angiogenic potential in vitro and therefore might stimulate bone regeneration in vivo. To assess this prospect, the study targets at heparin-modified mineralized collagen scaffolds functionalized with naturally occurring bioactive factor mixtures and/or rhBMP-2. These scaffolds were implanted into a 2-mm segmental femoral defect in mice and analyzed in respect to newly formed bone volume (BV) and bone mineral density (BMD) by micro-computed tomography scans after an observation period of 6 weeks. To rate the degree of defect healing, the number of vessels, and the activity of osteoclasts and osteoblasts were analyzed histologically. The sole application of bioactive factor mixtures is inferior to the use of the recombinant growth factor rhBMP-2 regarding BV and degree of defect healing. A higher rhBMP-2 concentration or the combination with bioactive factor mixtures does not lead to a further enhancement in defect healing. Possibly, a synergistic effect can be achieved by further concentration or a prolonged release of bioactive factor mixtures. STATEMENT OF SIGNIFICANCE: : The successful therapy of extended bone defects is still a major challenge in clinical routine. In this study we investigated the bone regenerative potential of naturally occuring bioactive factor mixtures derived from platelet concentrates, adipose tissue and cell secretomes as a cheap and promising alternative to recombinant growth factors in a murine segmental bone defect model. The mixtures alone were not able to induce complete bridging of the bone defect, but in combination with bone morphogenetic protein 2 bone healing seemed to be more physiological. The results show that naturally occuring bioactive factor mixtures are a promising add-on in a clinical setting.

Fast Degradable Calcium Phosphate Cement for Maxillofacial Bone Regeneration.

The aim of this preclinical study was to test the applicability of calcium phosphate cement (CPC)-poly(lactic-co-glycolic acid) (PLGA)-carboxymethylcellulose (CMC) as a bone substitute material for guided bone regeneration (GBR) procedures in a clinically relevant mandibular defect model in minipigs. In the study, a predicate device (i.e., BioOss®) was included for comparison. Critical-sized circular mandibular bone defects were created and filled with either CPC-PLGA-CMC without coverage with a GBR membrane or BioOss covered with a GBR membrane and left to heal for 4 and 12 weeks to obtain temporal insight in material degradation and bone formation. Bone formation increased significantly for both CPC-PLGA-CMC and BioOss with increasing implantation time. Further, no significant differences were found for bone formation at either 4 or 12 weeks between CPC-PLGA-CMC and BioOss. Finally, bone substitute material degradation increased significantly for both CPC-PLGA-CMC and BioOss from 4 to 12 weeks of implantation, showing the highest degradation for CPC-PLGA-CMC (∼85%) compared to BioOss (∼12%). In conclusion, this minipig study showed that CPC-PLGA-CMC can be used as a bone-grafting material and stimulates bone regeneration to a comparable extent as with BioOss particles. Importantly, CPC-PLGA-CMC degrades faster compared to BioOss, is easier to apply into a bone defect, and does not need the use of an additional GBR membrane. Consequently, the data support the further investigation of CPC-PLGA-CMC in human clinical trials. Impact statement Guided bone regeneration (GBR) is a frequently used dental surgical technique to regenerate the alveolar ridge to allow stable implant installation. However, stabilization of the GBR membrane and avoidance of bone graft movement remain a challenge. Consequently, there is need for the development of alternative materials to be used in GBR procedures that are easier to apply and induce predictable bone regeneration. In this minipig study, we focused on the applicability of calcium phosphate cement-poly(lactic-co-glycolic acid)-carboxymethylcellulose as an alternative bone substitute material for GBR procedures without the need of an additional GBR membrane.

Apoptotic Vesicles Regulate Bone Metabolism via the miR1324/SNX14/SMAD1/5 Signaling Axis.

Mesenchymal stem cells (MSCs) are widely used in the treatment of diseases. After their in vivo application, MSCs undergo apoptosis and release apoptotic vesicles (apoVs). This study investigates the role of apoVs derived from human bone marrow mesenchymal stem cells (hBMMSCs) in bone metabolism and the molecular mechanism of the observed effects. The results show that apoVs can promote osteogenesis and inhibit osteoclast formation in vitro and in vivo. ApoVs may therefore attenuate the bone loss caused by primary and secondary osteoporosis and stimulate bone regeneration in areas of bone defect. The mechanisms responsible for apoV-induced bone regeneration include the release of miR1324, which inhibit expression of the target gene Sorting Nexin 14 (SNX14)and thus activate the SMAD1/5 pathway in target cells. Given that MSC-derived apoVs are easily obtained and stored, with low risks of immunological rejection and neoplastic transformation, The findings suggest a novel therapeutic strategy to treat bone loss, including via cell-free approaches to bone tissue engineering.

Stimuli-responsive piezoelectricity in electrospun polycaprolactone (PCL)/Polyvinylidene fluoride (PVDF) fibrous scaffolds for bone regeneration

Polymeric scaffolds are a determinant part of modern tissue engineering owing to their great diversity, adaptability, and processability. Interestingly, the physical properties of these scaffolds, e.g., porosity, mechanical properties, and biocompatibility, can be tuned to make them smart and stimuli-responsive. In this regard, piezoelectric materials can be applied to stimulate bone regeneration by converting mechanical impulses to electrical signals. In the present research, fibers made of various blend ratios of polyvinylidene fluoride (PVDF)/polycaprolactone (PCL) were fabricated, investigated and optimized to promote bone regeneration. Uniform fibers containing β-phase PVDF were obtained due to the simultaneous stretching and high voltage applied during electrospinning. Furthermore, components interaction, crystallinity, and piezoelectric behavior were estimated through fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and piezometery, respectively. The samples showed improved wettability and controlled biodegradability, and the piezoelectric charge output reached up to 7.5 pC/N in the sample containing 70 wt% PVDF. At the same time, these scaffolds could provide mechanical properties close to the native bone tissue relying on the PVDF component. In vitro assessments demonstrated that the composite scaffolds were biocompatible and could support cell attachment and proliferation. Moreover, their piezoelectric behavior promoted stem cell differentiation into osteoblasts. Considering the obtained results, the potential of piezoelectric PVDF/PCL blend fibers for bone scaffolds is indisputable.

Optimization of an Injectable, Resorbable, Bioactive Cement Able to Release the Anti-Osteoclastogenic Biomolecule ICOS-Fc for the Treatment of Osteoporotic Vertebral Compression Fractures.

Vertebral compression fractures are typical of osteoporosis and their treatment can require the injection of a cement through a minimally invasive procedure to restore vertebral body height. This study reports the development of an injectable calcium sulphate-based composite cement able to stimulate bone regeneration while inhibiting osteoclast bone resorption. To this aim, different types of strontium-containing mesoporous glass particles (Sr-MBG) were added to calcium sulphate powder to impart a pro-osteogenic effect, and the influence of their size and textural features on the cement properties was investigated. Anti-osteoclastogenic properties were conferred by incorporating into poly(lactic-co-glycolic)acid (PLGA) nanoparticles, a recombinant protein able to inhibit osteoclast activity (i.e., ICOS-Fc). Radiopaque zirconia nanoparticles (ZrO2) were also added to the formulation to visualize the cement injection under fluoroscopy. The measured cement setting times were suitable for the clinical practice, and static mechanical testing determined a compressive strength of ca. 8 MPa, comparable to that of human vertebral bodies. In vitro release experiments indicated a sustained release of ICOS-Fc and Sr2+ ions up to 28 days. Overall, the developed cement is promising for the treatment of vertebral compression fractures and has the potential to stimulate bone regeneration while releasing a biomolecule able to limit bone resorption.

ОПЫТ ПРИМЕНЕНИЯ ПЛАЗМЫ ОБОГАЩЕННОЙ ТРОМБОЦИТАМИ ПРИ ЛЕЧЕНИИ ПАЦИЕНТОВ С ОБШИРНЫМИ РАНЕВЫМИ ДЕФЕКТАМИ

Allogeneic plasma enriched with platelets (hereinafter ALPEP/PRP) is often used in various branches of medicine. The scope of application of PRP therapy varies from stimulation of bone regeneration, healing of wounds and ulcers, mus-culoskeletal injuries to increasing the possibilities in the engraftment of various types of transplants. Due to the native properties of platelet-enriched plasma, its introduction into the human body is one of the promising manipulations in tissue regeneration. After the destruction of platelets, ALPEEP contains α-granules, from which, after activation, many factors are released, such as transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VGFF) and epi-dermal growth factor (EGF).

Positive Effect of Platelet-Rich Plasma on Neoureterocystostomy in Rats: An Experimental Study.

Some of the most common problems after kidney transplant are urologic complications, including ureterocystoanastomosis leakage and stenosis with the development of severe renal graft complications. Isolated plasma contains active substances that cause the activation of various growth factors for the processes of tissue repair or regeneration, has an anti- inflammatory effect, activates angiogenesis, and reduces the risk of infectious complications. Platelet-rich plasma is actively used to stimulate bone regeneration, heal wounds and ulcers on the skin, enhance reconstruction of the larynx and trachea, and ameliorate urethral damage, among other uses. This study was developed to evaluate the positive effect of platelet-rich plasma on the healing process of an anastomotic wound in a model of ureterocystoanas-tomosis in rats. We randomized 14 Wistar albino male rats into 2 groups: group 1 included 7 rats that received platelet-rich plasma after ureterocystostomy; group 2 was the control group and included 7 rats that underwent ureterocystostomy without platelet-rich plasma. On postoperative day 7, all animals were euthanized, and the anastomosis area was resected for determination of the tissue hydroxyproline levels and histopathology examination. Tissue hydroxyproline levels were 767 ± 62.9 μg/g in group 1 and 256 ± 28.0 μg/g in group 2. Tissue hydroxyproline levels were significantly higher in group 1 compared with group 2 (P < .05). There were no significant differences in epithelial damage, acute inflammation, or fibrosis between the tissue samples of both groups. The results of this study show that the use of platelet-rich plasma during ureterocystostomy produces a positive effect. Our further research will be devoted to the use of autologous platelet-rich plasma in ureterocystostomy in big models.

LIPUS accelerates bone regeneration via HDAC6-mediated ciliogenesis

Delayed fracture union and nonunion are common complications of fracture encountered, while Low-intensity pulsed ultrasound (LIPUS) can stimulate bone regeneration. Still, the underlying mechanism of LIPUS on bone regeneration has been poorly understood, which resulted in varied outcomes in the clinic. Therefore, figuring out the mechanism of LIPUS on bone regeneration can lay the foundation for better use of LIPUS in clinical bone regenerative therapies. In this study, we created transgenic mice to reveal the relationship between the periosteal cells' fate and the number of ciliated cells under the LIPUS stimulation. In vitro, we isolated the periosteal cell and aim to figure out the relationship between LIPUS and HDAC6-mediated ciliogenesis and find out a potential target for LIPUS-based bone regeneration strategies. The results showed that LIPUS promoted femoral bone defect regeneration and enhanced osteogenic differentiation of Prrx1+ cells. However, these pro-effects were significantly weakened when the Prrx1+ cell's primary cilia were knocked down. Besides, LIPUS stimulated the formation of Prrx1+ cells' primary cilia in the bone defect microenvironment. In vitro, the results supported that LIPUS enhanced the osteogenic differentiation of Prrx1+ cells through HDAC6-mediated ciliogenesis. In conclusion, λ LIPUS could promote the osteogenic differentiation of Prrx1+ cells to stimulate bone regeneration and inhibit the expression of HDAC6 to increase the prevalence of primary cilia in Prrx1+ cells. LIPUS could enhance the osteogenic differentiation of Prrx1+ cells mainly through HDAC6-mediated ciliogenesis.

Electrospun fibers coated with nanostructured biomimetic hydroxyapatite: A new platform for regeneration at the bone interfaces

Reconstruction of gradient organic/inorganic tissues is a challenging task in orthopaedics. Indeed, to mimic tissue characteristics and stimulate bone regeneration at the interface, it is necessary to reproduce both the mineral and organic components of the tissue ECM, as well as the micro/nano-fibrous morphology. To address this goal, we propose here novel biomimetic patches obtained by the combination of electrospinning and nanostructured bone apatite. In particular, we deposited apatite on the electrospun fibers by Ionized Jet Deposition, a plasma-assisted technique that allows conformal deposition and the preservation in the coating of the target's stoichiometry. The damage to the substrate and fibrous morphology is a polymer-dependent aspect, that can be avoided by properly selecting the substrate composition and deposition parameters. In fact, all the tested polymers (poly(l-lactide), poly(D,l-lactide-co-glycolide, poly(ε-caprolactone), collagen) were effectively coated, and the morphological and thermal characterization revealed that poly(ε-caprolactone) suffered the least damage. The coating of collagen fibers, on the other hand, destroyed the fiber morphology and it could only be performed when collagen is blended with a more resistant synthetic polymer in the nanofibers. Due to the biomimetic composition and multiscale morphology from micro to nano, the poly(ε-caprolactone)-collagen biomimetic patches coated with bone apatite supported MSCs adhesion, patch colonization and early differentiation, while allowing optimal viability. The biomimetic coating allowed better scaffold colonization, promoting cell spreading on the fibers.

Simvastatin Embedded into Poly(Lactic-Co-Glycolic Acid)-Based Scaffolds in Promoting Preclinical Bone Regeneration: A Systematic Review

Simvastatin embedded into poly(lactic-co-glycolic acid) (PLGA)-based scaffolds can stimulate bone regeneration in preclinical models. However, the ideal pharmacological dose has not been evaluated. This systematic review reports on the simvastatin doses used in preclinical studies and evaluates the regeneration of critical-sized bone defects. References were selected in a two-phase process. Electronic databases (Embase, LILACS, LIVIVO, PubMed, SCOPUS, and Web of Science) and grey literature databases (Google Scholar, Open Grey, and ProQuest) were searched until September 2022. The risk of bias was considered to be low based on the SYRCLE tool. We identified four studies in rat, two in parietal and two in calvaria bone, one in mouse parietal bone, and one in rabbit femur bone. Simvastatin, ranging from 8 to 100 µg, significantly increased bone formation in five studies, as compared to the scaffold alone based on µ-computed tomography, histomorphometric, and radiography analysis. The median increase in bone formation caused by simvastatin was 2.1-fold compared to the PLGA-based scaffold alone. There was, however, no significant correlation between the relative bone gain and the doses of simvastatin (p = 0.37). The data suggest that relatively lower doses of simvastatin can consistently promote preclinical bone regeneration. However, the interpretation of these data must consider the heterogenicity of the PLGA-scaffolds, the defect anatomy, the observation period, and the evaluation method.

Utilization of Nanotechnology to Improve Bone Health in Osteoporosis Exploiting Nigella sativa and Its Active Constituent Thymoquinone.

Osteoporosis, a chronic bone disorder, is one of the leading causes of fracture and morbidity risk. Numerous medicinally important herbs have been evaluated for their efficacy in improving bone mass density in exhaustive preclinical and limited clinical studies. Nigella sativa L. has been used as local folk medicine, and traditional healers have used it to manage various ailments. Its reported beneficial effects include controlling bone and joint diseases. The present manuscript aimed to provide a sound discussion on the pharmacological evidence of N. sativa and its active constituent, thymoquinone, for its utility in the effective management of osteoporosis. N. sativa is reported to possess anti-IL-1 and anti-TNF-α-mediated anti-inflammatory effects, leading to positive effects on bone turnover markers, such as alkaline phosphatase and tartrate-resistant acid phosphatase. It is reported to stimulate bone regeneration by prompting osteoblast proliferation, ossification, and decreasing osteoclast cells. Thymoquinone from N. sativa has exhibited an antioxidant effect on bone tissue by reducing the FeNTA-induced oxidative stress. The present manuscript highlights phytochemistry, pharmacological effect, and the important mechanistic perspective of N. sativa and its active constituents for the management of osteoporosis. Further, it also provides sound discussion on the utilization of a nanotechnology-mediated drug delivery approach as a promising strategy to improve the therapeutic performance of N. sativa and its active constituent, thymoquinone, in the effective management of osteoporosis.

Halide-containing bioactive glasses enhance osteogenesis in vitro and in vivo

The application of bone substitutes to reconstruct bone defects is a strategy for repairing alveolar bone loss caused by periodontal disease. Bioactive glasses (BGs) are attractive synthetic bone substitutes owing to their abilities to degrade, form bone-like mineral and stimulate bone regeneration. Our previous studies showed that the incorporation of fluoride into alkali-free bioactive silicate glass promoted osteogenesis to some extent in vitro, while the incorporation of chloride facilitated glass degradation and accelerated the formation of hydroxyapatite. However, whether there is a synergistic effect of incorporating fluoride and chloride on further enhancement of osteogenesis and angiogenesis in vitro and in vivo was not known. Therefore, we synthesized three halide-containing BGs with fluoride only, or chloride only, or mixed fluoride and chloride, investigated their physicochemical properties and osteogenic and angiogenic effects both in vitro and in vivo. The results showed that the addition of both fluoride and chloride in a bioactive silicate glass could combine the structural roles of both, leading to a faster apatite formation than the glass with the presence of fluoride only and a more stable fluorapatite formation than the glass with the presence of chloride only, which formed hydroxyapatite upon immersion. The studied BGs were cytocompatible, as suggested by the cytotoxicity evaluation of hPDLSCs cultivated in the extracted BGs-conditioned culture media. More importantly, these BGs stimulated osteogenic differentiation of hPDLSCs without adding growth factors as indicated by the fact that BGs-conditioned media up-regulated the expression of BMP-2, OPN and VEGF of hPDLSCs and promoted the formation of bone nodules and collagen in vitro. By comparison, the incorporation of fluoride facilitated the expression of osteogenic-related biomarkers and bone nodule formation preferentially, while the incorporation of chloride induced the expression of angiogenic-related biomarkers and collagen formation. The in vivo investigation results demonstrated that the developed halide-containing BGs accelerated the process of bone regeneration, while the glass with mixed fluoride and chloride showed the most significant promotion effect among the three BGs. Therefore, our findings revealed a synergistic effect of incorporating fluoride and chloride into a BG on osteogenesis and angiogenesis in vitro and in vivo and highlighted the potential of fluoride and chloride containing bioactive glasses being bone substitutes for clinical use.

Available methods to enhance regenerative potential of plastic materials for bone defects replacement in orthopedics. Part 3. Use of autologous human red bone marrow

The previous two articles described the use of platelet-rich plasma and platelet lysate. This part of the literature review examines the mechanism of red bone marrow action, indications and contraindications for its use. The results of treatment for delayed consolidation of bone fractures are also described. Hematopoietic stem cells give rise to all cellular components of the circulating blood, such as red blood cells, lymphocytes, neutrophils, and platelets. The most rational way to stimulate bone regeneration is to use the patient's own biological material. The aim of this article is to summarize the results of treatment using autologus bone marrow to improve bone regenerative potential in orthopaedics.

Use of hyaluronic acid for regeneration of maxillofacial bones

Hyaluronic acid (HA) has been widely used in medicine and is currently of particular interest to maxillofacial surgeons. Several applications have been introduced, including those in which HA is used as a scaffold for bone regeneration, either alone or in combination with other grafting materials, to enhance bone growth. This review aims to analyze the available literature on the use of HA for maxillofacial bone regenerative procedures including socket preservation, sinus augmentation, and ridge augmentation. Medline and PubMed databases were searched for relevant reports published between January 2000 and April 2021. Nine publications describing the use of HA to augment bone volume were identified. Although further studies are needed, these findings are encouraging as they suggest that HA could be used effectively used, in combination with graft materials, in maxillofacial bone regenerative procedures. HA facilitates manipulation of bone grafts, improves handling characteristics and promotes osteoblast activity that stimulates bone regeneration and repair.

Non-viral CRISPR activation system targeting VEGF-A and TGF-β1 for enhanced osteogenesis of pre-osteoblasts implanted with dual-crosslinked hydrogel.

Healing of large calvarial bone defects remains challenge but may be improved by stimulating bone regeneration of implanted cells. The aim of this study is to specially co-activate transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VEGF-A) genes expressions in pre-osteoblast MC3T3-E1 cells through the non-viral CRISPR activation (CRISPRa) system to promote osteogenesis. A cationic copolymer carrying nucleus localizing peptides and proton sponge groups dimethyl-histidine was synthesized to deliver CRISPRa system into MC3T3-E1 cells with high cellular uptake, lysosomal escape, and nuclear translocation, which activated VEGF-A and TGF-β1 genes expressions and thereby additively or synergistically induced several osteogenic genes expressions. A tunable dual-crosslinked hydrogel was developed to implant the above engineered cells into mice calvaria bone defect site to promote bone healing in vivo. The combination of multi-genes activation through non-viral CRISPRa system and tunable dual-crosslinked hydrogel provides a versatile strategy for promoting bone healing with synergistic effect.

Use of hyaluronic acid for regeneration of maxillofacial bones: A review

Purpose: Hyaluronic acid (HA) has been used widely in medicine and is currently of particular interest to maxillofacial surgeons. Several applications have been introduced, including those in which HA is used as a scaffold for bone regeneration both alone and in combination with other grafting materials to enhance bone growth. This review aims to analyze the available literature on the use of HA for maxillofacial bone augmentation for prosthetic-driven implant placement procedures. This article also aims to review the specific advantages, applications, and graft materials associated with HA use. Materials and Methods: Medline and PubMed databases were searched for relevant reports published between January 2000 and December 2021. Results and Discussion: Nine publications describing the use of HA to augment bone volume were identified. Administration of HA facilitates surgical manipulation of the graft and promotes osteoblast activity that stimulates bone regeneration and repair. Conclusion: Although further studies are needed, these findings are encouraging, as they suggest that HA might be used effectively together with additional graft materials in maxillofacial bone augmentation procedures.​