A Biomimetic Peptide Functions as Specific Extracellular Matrix for Quiescence of Stem Cells against Intervertebral Disc Degeneration.

Maintaining quiescence of stem cells is a potential way to decrease cell nutrition demand for restoring the organization. Herein, a biomimetic peptide to maintain quiescence of stem cells through C-X-C motif chemokine ligand 8 (CXCL8)-C-X-C motif chemokine receptor 1 (CXCR1) pathway against intervertebral disc degeneration (IVDD) is developed. First, it is confirmed that quiescence can be induced via inhibiting phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in nucleus pulposus stem cells (NPSCs). Meanwhile, it is well known that CXCR1, a chemokine receptor, can be targeted by CXCL8, resulting in cell proliferation via activating PI3K/Akt/mTOR pathway. Second, a biomimetic peptide (OAFF) that can bind to CXCR1 and form fibrous networks on NPSCs, mimicking extracellular matrix formation is developed. The multivalent effect and long-term binding to CXCR1 on NPSCs of OAFF fibers offer forcefully competitive inhibition with natural CXCL8, which induces NPSCs quiescence and ultimately overcomes obstacle in intradiscal injection therapy. In rat caudal disc puncture model, OAFF nanofibers still maintain at 5 weeks after operation and inhibit degeneration process of intervertebral disc in terms of histopathology and imageology. In situ fibrillogenesis of biomimetic peptide on NPSCs provides promising stem cells for intradiscal injection therapy against IVDD.

Puerarin inhibits the osteoclastogenesis by inhibiting RANKL-dependent and -independent autophagic responses.

BACKGROUND: Puerarin exerts therapeutic effect on osteoporosis due to its inhibitory effect on the formation of osteoclasts. Puerarin is also widely established as an autophagy inhibitor. The study aimed to investigate the significance of autophagy in Puerarin-treated osteoclast formation. METHODS: Osteoclast precursors (OCPs) derived from bone marrow-derived macrophages (BMMs) were treated with Puerarin along with RANKL or without RANKL, and then the autophagic parameters of OCPs (including autophagic proteins, LC3 transformation, autophagosome or LC3-puncta) were observed through Western Blotting, Transmission Electron Microscopy and Immunofluorescence assays. Next, after using overexpression vectors of autophagic genes (Atg7, Atg5 and BECN1) to alter autophagy activity, OCP proliferation was measured by Ethynyl deoxyuridine (EdU) assays and Cell Counting Kit-8 (CCK-8) kit, and osteoclast differentiation was assessed by Tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: The results showed that Puerarin could directly inhibit the autophagy and proliferation of OCPs. Importantly, overexpression of autophagic genes Atg5, Atg7 and BECN1 reversed Puerarin-inhibited OCP autophagy and proliferation. What's more, RANKL could promote the autography of OCPs, which was recovered by Puerarin treatment. Interestingly, different from single-Puerarin treatment, we found that in the presence of RANKL, only BECN1 overexpression significantly reversed Puerarin-inhibited osteoclast differentiation and OCP autophagy. CONCLUSION: In conclusion, Puerarin could inhibit the OCP autophagy in the presence or absence of RANKL, which blocked the OCP proliferation and osteoclast differentiation respectively. Moreover, BECN1 plays an essential role in Puerarin-inhibited osteoclastogenesis. Our study provides potential clue to further complete the intrinsic mechanism of Puerarin in treating osteoporosis.

Flexible Fabrication and Hybridization of Bioactive Hydrogels with Robust Osteogenic Potency.

Osteogenic scaffolds reproducing the natural bone composition, structures, and properties have represented the possible frontier of artificially orthopedic implants with the great potential to revolutionize surgical strategies against the bone-related diseases. However, it is difficult to achieve an all-in-one formula with the simultaneous requirement of favorable biocompatibility, flexible adhesion, high mechanical strength, and osteogenic effects. Here in this work, an osteogenic hydrogel scaffold fabricated by inorganic-in-organic integration between amine-modified bioactive glass (ABG) nanoparticles and poly(ethylene glycol) succinimidyl glutarate-polyethyleneimine (TSG-PEI) network was introduced as an all-in-one tool to flexibly adhere onto the defective tissue and subsequently accelerate the bone formation. Since the N-hydroxysuccinimide (NHS)-ester of tetra-PEG-SG polymer could quickly react with the NH2-abundant polyethyleneimine (PEI) polymer and ABG moieties, the TSG-PEI@ABG hydrogel was rapidly formed with tailorable structures and properties. Relying on the dense integration between the TSG-PEI network and ABG moieties on a nano-scale level, this hydrogel expressed powerful adhesion to tissue as well as durable stability for the engineered scaffolds. Therefore, its self-endowed biocompatibility, high adhesive strength, compressive modulus, and osteogenic potency enabled the prominent capacities on modulation of bone marrow mesenchymal stem cell (BMSCs) proliferation and differentiation, which may propose a potential strategy on the simultaneous scaffold fixation and bone regeneration promotion for the tissue engineering fields.

pH-Responsive Delivery of H2 through Ammonia Borane-Loaded Hollow Polydopamine for Intervertebral Disc Degeneration Therapy.

An imbalance in oxidative and inflammatory regulation is the main contributor to intervertebral disc degeneration (IDD). Hydrogen (H2) therapy is a promising antioxidation and anti-inflammatory approach. However, the key to the treatment is how to maintain the long-term effective H2 concentration in the intervertebral disc (IVD). Therefore, we developed a pH-responsive delivery of H2 through ammonia borane-loaded hollow polydopamine (AB@HPDA) for IDD therapy, which has sufficient capacity to control long-term H2 release in an acid-dependent manner in degenerative IVD. The characterization, toxicity, and pH-responsive H2 release of AB@HPDA was detected in vitro. The metabolization of AB@HPDA in the degenerated IVD was tested by in vivo imaging. The therapeutic effect of AB@HPDA on IDD was tested in vivo by X-ray, MRI, water content of the disc, and histological changes. Nuclear extracellular matrix (ECM) components, oxidative stress, and inflammation were also tested to explore potential therapeutic mechanisms. AB@HPDA has good biocompatibility at concentrations less than 500 µg/mL. The H2 release of AB@HPDA was pH responsive. Therefore, AB@HPDAs can provide efficient hydrogen therapy with controlled H2 release in response to the acidic degenerated IVD microenvironment. The metabolization of AB@HPDA in IVD was slow and lasted up to 11 days. HPDA and AB@HPDA significantly inhibited IDD, as tested by X-ray, MRI, disc water content, and histology (P < 0.05). pH-responsive H2 delivery through AB@HPDAs has the potential to efficiently treat IDD by inhibiting ECM degradation and rebalancing oxidative stress and inflammation in degenerative IVDs.

Biomimetic hydrogel derived from decellularized dermal matrix facilitates skin wounds healing.

Cutaneous wound healing affecting millions of people worldwide represents an unsolvable clinical issue that is frequently challenged by scar formation with dramatical pain, impaired mobility and disfigurement. Herein, we prepared a kind of light-sensitive decellularized dermal extracellular matrix-derived hydrogel with fast gelling performance, biomimetic porous microstructure and abundant bioactive functions. On account of its excellent cell biocompatibility, this ECM-derived hydrogel could induce a marked cellular infiltration and enhance the tube formation of HUVECs. In vivo experiments based upon excisional wound splinting model showed that the hydrogel prominently imparted skin wound healing, as evidenced by notably increased skin appendages and well-organized collagen expression, coupled with significantly enhanced angiogenesis. Moreover, the skin regeneration mediated by this bioactive hydrogel was promoted by an accelerated M1-to-M2 macrophage phenotype transition. Consequently, the decellularized dermal matrix-derived bioactive hydrogel orchestrates the entire skin healing microenvironment to promote wound healing and will be of high value in treatment of cutaneous wound healing. As such, this biomimetic ddECMMA hydrogel provides a promising versatile opinion for the clinical translation.

Neuroprotective Effects of Curcumin against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury in Cultured Primary Rat Astrocyte by Improving Mitochondrial Function and Regulating the ERK Signaling Pathway.

Objectives: Curcumin (Cur) is a natural polyphenol isolated from turmeric and has potent anti-inflammatory and antioxidant activities. This study aimed to explore the effects and possible mechanisms of curcumin on oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in cultured rat astrocyte primary cells. Methods: After screening for effective doses, the cultured rat astrocyte primary cells were divided into three groups: control, OGD/R, and OGD/R + curcumin (10 µM, 20 µM, and 40 µM). Cell viability was detected using CCK8 assays. The level of malondialdehyde and superoxide dismutase activity was determined using commercial kits. The endothelial nitric oxide synthase and adenosine triphosphate concentrations were determined by enzyme-linked immunosorbent assay. The mRNA levels of the inflammatory indexes interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1ß were evaluated by quantitative reverse-transcription polymerase chain reaction. Annexin V-fluorescein isothiocyanate/propidium iodide was used to detect apoptosis. JC-1 was used to assess the mitochondrial membrane potential. The protein expression of apoptosis-related proteins (B-cell lymphoma-2 (Bcl-2), BCL-2-associated X (Bax), and cleaved caspase 3), mitochondria-related proteins (dynamin-related protein 1 (DRP1), phosphorylated DRP1 (p-DRP1), and mitofusin 2), and essential proteins of the extracellular signal-regulated kinase (ERK) signaling pathway (ERK1/2, p-ERK1/2) were analyzed by western blot. Results: Our data indicated that curcumin reversed OGD/R-induced cell viability loss, oxidative stress, inflammatory cytokine production, and cell apoptosis in a dose-dependent manner. Furthermore, curcumin attenuated OGD/R-induced mitochondrial dysfunction and ERK1/2 phosphorylation in a dose-dependent manner. Conclusions: Curcumin protected against OGD/R-induced injury in rat astrocyte primary cells through improving mitochondrial function and regulating the ERK signaling pathway.

Construction of Biocompatible Hydrogel Scaffolds With a Long-Term Drug Release for Facilitating Cartilage Repair.

In tissue engineering, hydrogel scaffolds allow various cells to be cultured and grown in vitro and then implanted to repair or replace the damaged areas. Here in this work, kartogenin (KGN), an effectively chondro-inductive non-protein bioactive drug molecule, was incorporated into a composite hydrogel comprising the positively charged chitosan (CS) and methacrylated gelatin (GelMA) polymers to fabricate appropriate microenvironments of bone marrow mesenchymal stem cells (BMSCs) for cartilage regeneration. Based on the combination of physical chain entanglements and chemical crosslinking effects, the resultant GelMA-CS@KGN composite hydrogels possessed favorable network pores and mechanical strength. In vitro cytotoxicity showed the excellent biocompatibility for facilitating the cell growth, adhesion, proliferation, and differentiation. The long-term sustainable KGN release from the hydrogel scaffolds in situ promoted the chondrogenic differentiation that can be employed as an alternative candidate for cartilage tissue regeneration.

Fabrication of Naturally Derived Double-Network Hydrogels With a Sustained Aspirin Release System for Facilitating Bone Regeneration.

Continuous efforts on pursuit of effective drug delivery systems for engineering hydrogel scaffolds is considered a promising strategy for the bone-related diseases. Here, we developed a kind of acetylsalicylic acid (aspirin, ASA)-based double-network (DN) hydrogel containing the positively charged natural chitosan (CS) and methacrylated gelatin (GelMA) polymers. Combination of physical chain-entanglement, electrostatic interactions, and a chemically cross-linked methacrylated gelatin (GelMA) network led to the formation of a DN hydrogel, which had a suitable porous structure and favorable mechanical properties. After in situ encapsulation of aspirin agents, the resulting hydrogels were investigated as culturing matrices for adipose tissue-derived stromal cells (ADSCs) to evaluate their excellent biocompatibility and biological capacities on modulation of cell proliferation and differentiation. We further found that the long-term sustained ASA in the DN hydrogels could contribute to the anti-inflammation and osteoinductive properties, demonstrating a new strategy for bone tissue regeneration.

Formulation of pH-responsive PEGylated nanoparticles with high drug loading capacity and programmable drug release for enhanced antibacterial activity.

In the current global crisis of antibiotic resistance, delivery systems are emerging to combat resistant bacteria in a more efficient manner. Despite the significant advances of antibiotic nanocarriers, many challenges like poor biocompatibility, premature drug release, suboptimal targeting to infection sites and short blood circulation time are still challenging. To achieve targeted drug delivery and enhance antibacterial activity, here we reported a kind of pH-responsive nanoparticles by simply self-assembly of an amphiphilic poly(ethylene glycol)-Schiff-vancomycin (PEG-Schiff-Van) prodrug and free Van in one drug delivery system. The acid-liable Schiff base furnished the PEG-Schiff-Van@Van with good storage stability in the neutral environment and susceptible disassembly in response to faintly acidic condition. Notably, on account of the combination of physical encapsulation and chemical conjugation of vancomycin, these nanocarriers with favorable biocompatibility and high drug loading capacity displayed a programmed drug release behavior, which was capable of rapidly reaching high drug concentration to effectively kill the bacteria at an early period and continuously exerting an bacteria-sensitive effect whenever needed over a long period. In addition, more Schiff-base moieties within the PEG-Schiff-Van@Van nanocarriers may also make great contributions on promoting the antimicrobial activity. Using this strategy, this system was designed to have programmable structural destabilization and sequential drug release due to changes in pH that were synonymous with bacterial infection sites, thereby presenting prominent antibacterial therapy both in vitro and in vivo. This work represents a synergistic strategy on offering important guidance to rational design of multifunctional antimicrobial vehicles, which would be a promising class of antimicrobial materials for potential clinical translation.

Alendronate-functionalized double network hydrogel scaffolds for effective osteogenesis.

Development of artificial bone substitutes mimicking the extracellular matrix is a promising strategy for bone repair and regeneration. In views of the actual requirement of biomechanics, biodegradability, and bioactivity, herein, a double-network (DN) hydrogel was constructed by interspersing a methacrylated gelatin (GelMA) network into alendronate (ALN)-modified oxidized alginate (OSA) network via Schiff base reaction and photo-crosslinking process to promote in situ bone regeneration. This GelMA@OSA-ALN DN hydrogel possessed favorable network and pores, good biocompatibility, and enhanced biomechanics. Notably, the introduction of Schiff base furnished the ND hydrogel scaffold with pH-responsive biodegradation and sustained ALN drug release delivery, which could provide effective bioactivity, upregulate osteogenesis-related genes, and promote the cell viability, growth, proliferation, and osteogenesis differentiation for bone regeneration. Therefore, we provide a new insight to develop functional DN hydrogel scaffold toward governing the on-demand drug release and achieving the stem cell therapy, which will be developed into the minimally invasive gelling system to prolong local delivery of bisphosphonates for the bone-related diseases.

Recent Trends in the Development of Bone Regenerative Biomaterials.

The goal of a biomaterial is to support the bone tissue regeneration process at the defect site and eventually degrade in situ and get replaced with the newly generated bone tissue. Biomaterials that enhance bone regeneration have a wealth of potential clinical applications from the treatment of non-union fractures to spinal fusion. The use of bone regenerative biomaterials from bioceramics and polymeric components to support bone cell and tissue growth is a longstanding area of interest. Recently, various forms of bone repair materials such as hydrogel, nanofiber scaffolds, and 3D printing composite scaffolds are emerging. Current challenges include the engineering of biomaterials that can match both the mechanical and biological context of bone tissue matrix and support the vascularization of large tissue constructs. Biomaterials with new levels of biofunctionality that attempt to recreate nanoscale topographical, biofactor, and gene delivery cues from the extracellular environment are emerging as interesting candidate bone regenerative biomaterials. This review has been sculptured around a case-by-case basis of current research that is being undertaken in the field of bone regeneration engineering. We will highlight the current progress in the development of physicochemical properties and applications of bone defect repair materials and their perspectives in bone regeneration.

Clinical and radiological outcomes of endoscopic foraminoplasty and decompression assisted with preoperative planning software for lumbar foraminal stenosis.

PURPOSE: To assess the clinical and radiological outcomes of using endoscopic foraminoplasty and decompression assisted with a preoperative planning software in the treatment of lumbar foraminal stenosis. METHODS: This retrospective study included 43 patients with lumbar foraminal stenosis (Jan 2018 and June 2019). These patients were divided into two groups. Patients in the conventional group (group A) underwent endoscopic lumbar foraminoplasty and decompression. Patients in the experimental group (group B) underwent the same surgery assisted with a preoperative software. The total operation time, puncture-channel establishment time, and the number of intraoperative fluoroscopic images taken were recorded. The Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) were administered preoperatively and postoperatively (at 1-month, 3-month, and 12-month follow-up). The modified MacNab criteria were used to assess the global outcome at 12-month follow-up. RESULTS: Patients in group B had shorter operation time, puncture-channel establishment time, and less number of intraoperative fluoroscopic images taken, as compared with group A. The VAS and ODI scores were significantly lower than pre-operation for both groups at all follow-ups. No significant difference was observed between these two groups. Based on the modified MacNab criteria, the excellent-to-good rate was 86.4% in group A and 90.5% in group B, respectively. After the operation, no patients had residual osteophytes in group B, while two patients still had residual osteophytes and foraminal stenosis in group A. CONCLUSION: For endoscopic surgery treating lumbar foraminal stenosis, using preoperative planning software could reduce the puncture-channel establishment time, operation time, and the number of intraoperative fluoroscopic images taken without affecting the clinical outcomes.

Morphology of Herniated Disc as a Predictor for Outcomes of Posterior Percutaneous Full-endoscopic Cervical Discectomy in Treating Cervical Spondylotic Radiculopathy.

OBJECTIVE: To quantitively characterize the morphology of cervical disc herniation (CDH) causing cervical spondylotic radiculopathy (CSR) and investigate whether the morphological features of CDH are associated with clinical outcomes in CSR patients treated by posterior percutaneous full-endoscopic cervical discectomy (PPECD). METHODS: This is a single-center retrospective study. Eighty-seven PPECD-treated patients meeting the inclusion criteria were included between May 2017 and May 2019. Based on preoperative T2-weighted magnetic resonance imaging (MRI), we designed and measured six morphological parameters of CDH for all patients to reflect its relative position to cervical spinal cord and protruding degree: DC-SC distance from the center of disc (DC) and the center of spinal cord (SC); DC-DP distance from the center of cervical disc (DC) to the peak of herniation (DP); internal diameter of the disc; axial length of CDH; central angle of CDH formed by central axes of CDH and spinal cord; the modified index of CDH. We recorded general information, neck disability index (NDI) scores, visual analog scale (VAS) scores of neck and arm of all patients preoperatively and postoperatively at 1-year follow-up. The association of preoperative general variables and morphological parameters with clinical outcomes were explored by utilizing logistic regression and receiver operating characteristic curve (ROC) analysis. RESULTS: The preoperative neck-VAS, arm-VAS, and NDI were significantly decreased after PPECD and remained at a low value at follow-up. In regards to the morphological parameters of CDH, the mean value of DC-SC distance, DC-DP distance, internal diameter of the disc, axial length of CDH, central angle of CDH, and modified index of CDH were 1.61 ± 0.30 cm, 1.66 ± 0.32cm, 1.04 ± 0.21 cm, 0.63 ± 0.19cm, 39.38° ± 11.94°, and 0.39 ± 0.24, respectively. For patients grouped by difference in the recovery rate of NDI and arm-VAS (excellent improved group, EI; and limited improved group, LI), there were no differences in the age, gender, surgical segments, and morphological parameters, except for the central angle of CDH. According to binary logistic regression analysis, only the preoperative central angle of CDH was significantly associated with postoperative NDI recovery (odds ratio: 0.873; 95% confidence interval: 0.819-0.931, P = 0.002). ROC analysis showed the optimal cut-off value of the central angle of CDH for predicting the postoperative improvement of functional outcomes is 33.788°. CONCLUSION: Preoperative morphology of CDH is related to the outcomes of CSR patients after PPECD. Patients with a large central angle of CDH (>33.788°) have more likelihood of ameliorating neurological symptoms of CSR. There is the potential to select the central angle of CDH as a predictor for outcomes of PPECD in treating CSR.

Advances of Naturally Derived and Synthetic Hydrogels for Intervertebral Disk Regeneration.

Intervertebral disk (IVD) degeneration is associated with most cases of cervical and lumbar spine pathologies, amongst which chronic low back pain has become the primary cause for loss of quality-adjusted life years. Biomaterials science and tissue engineering have made significant progress in the replacement, repair and regeneration of IVD tissue, wherein hydrogel has been recognized as an ideal biomaterial to promote IVD regeneration in recent years. Aspects such as ease of use, mechanical properties, regenerative capacity, and their applicability as carriers for regenerative and anti-degenerative factors determine their suitability for IVD regeneration. This current review provides an overview of naturally derived and synthetic hydrogels that are related to their clinical applications for IVD regeneration. Although each type has its own unique advantages, it rarely becomes a standard product in truly clinical practice, and a more rational design is proposed for future use of biomaterials for IVD regeneration. This review aims to provide a starting point and inspiration for future research work on development of novel biomaterials and biotechnology.

Recent Advances of Chitosan-Based Injectable Hydrogels for Bone and Dental Tissue Regeneration.

Traditional strategies of bone repair include autografts, allografts and surgical reconstructions, but they may bring about potential hazard of donor site morbidity, rejection, risk of disease transmission and repetitive surgery. Bone tissue engineering (BTE) is a multidisciplinary field that offers promising substitutes in biopharmaceutical applications, and chitosan (CS)-based bone reconstructions can be a potential candidate in regenerative tissue fields owing to its low immunogenicity, biodegradability, bioresorbable features, low-cost and economic nature. Formulations of CS-based injectable hydrogels with thermo/pH-response are advantageous in terms of their high-water imbibing capability, minimal invasiveness, porous networks, and ability to mold perfectly into an irregular defect. Additionally, CS combined with other naturally-derived or synthetic polymers and bioactive agents has proven to be an effective alternative to autologous bone and dental grafts. In this review, we will highlight the current progress in the development of preparation methods, physicochemical properties and applications of CS-based injectable hydrogels and their perspectives in bone and dental regeneration. We believe this review is intended as starting point and inspiration for future research effort to develop the next generation of tissue-engineering scaffold materials.