A Nature-Inspired Versatile Bio-Adhesive.

The application of most hydrogel bio-adhesives is greatly limited due to their high swelling, low underwater adhesion, and single function. Herein, a spatial multi-level physical-chemical and bio-inspired in-situ bonding strategy is proposed, to develop a multifunctional hydrogel bio-glue using polyglutamic acid (PGA), tyramine hydrochloride (TYR), and tannic acid (TA) as precursors and 4-(4,6-dimethoxytriazine-2-yl) -4-methylmorpholine hydrochloride(DMTMM) as condensation agent, which is used for tissue adhesion, hemostasis and repair. By introducing TYR and TA into the PGA chain, it is demonstrated that not only can the strong adhesion of bio-glue to the surface of various fresh tissues and wet materials be realized through the synergistic effect of spatial multi-level physical and chemical bonding, but also this glue can be endowed with the functions of anti-oxidation and hemostasis. The excellent performance of such bio-glue in the repair of the wound, liver, and cartilage is achieved, showing a great potential in clinical application for such bio-glue. This study will open up a brand-new avenue for the development of multifunctional hydrogel biological adhesive.

Supersaturation and Precipitation Applicated in Drug Delivery Systems: Development Strategies and Evaluation Approaches.

Supersaturation is a promising strategy to improve gastrointestinal absorption of poorly water-soluble drugs. Supersaturation is a metastable state and therefore dissolved drugs often quickly precipitate again. Precipitation inhibitors can prolong the metastable state. Supersaturating drug delivery systems (SDDS) are commonly formulated with precipitation inhibitors, hence the supersaturation is effectively prolonged for absorption, leading to improved bioavailability. This review summarizes the theory of and systemic insight into supersaturation, with the emphasis on biopharmaceutical aspects. Supersaturation research has developed from the generation of supersaturation (pH-shift, prodrug and SDDS) and the inhibition of precipitation (the mechanism of precipitation, the character of precipitation inhibitors and screening precipitation inhibitors). Then, the evaluation approaches to SDDS are discussed, including in vitro, in vivo and in silico studies and in vitro-in vivo correlations. In vitro aspects involve biorelevant medium, biomimetic apparatus and characterization instruments; in vivo aspects involve oral absorption, intestinal perfusion and intestinal content aspiration and in silico aspects involve molecular dynamics simulation and pharmacokinetic simulation. More physiological data of in vitro studies should be taken into account to simulate the in vivo environment. The supersaturation theory should be further completed, especially with regard to physiological conditions.

A bionic composite hydrogel with dual regulatory functions for the osteochondral repair.

Due to the avascular nature of cartilage, it is difficult to heal and regenerate spontaneously after injury. At present, tissue engineering has become a promising strategy for repairing damaged cartilage, but the use of seed cells and growth factors is limited. In addition, the importance of mechanical compatibility of scaffold materials is often ignored. In this study, osteochondral scaffold was designed as a bilayer structure with a dense γ-Polyglutamic acid/carboxymethyl chitosan/bacterial cellulose (PGA/CMCS/BC) hydrogel cartilage layer and a porous nano HA-containing PGA/CMCS/BC hydrogel osteogenic layer. In addition, bioactive ions were introduced into the hydrogel scaffold to adjust the mechanical and swelling properties of the material to match the mechanical properties of natural articular cartilage. At the same time, based on the structural characteristics of bone and cartilage, magnesium and copper ions were introduced into the double-layer hydrogel scaffold, respectively, to prepare the cartilage layer and the bone layer, which endowed the material with excellent antibacterial properties and achieved the purpose of the integrated repair of bone and cartilage. The results showed that, after adding magnesium ions, the tensile breaking strength of material was increased from 0.66 MPa to 1.37 MPa，the corresponding compression modulus of the material (strain 0-12%) increased from 0.15 MPa to 0.58 MPa whilst the maximum mass swelling rate decreased from 155% to 75%. The results of in vivo experiments show that the group with bioactive ions had a much better effect on the repair of osteochondral defects, compared with group without bioactive ions, demonstrating such double ion regulation strategy is a very practical strategy for the treatment of osteochondral defects.

Piezoelectric Effect of Antibacterial Biomimetic Hydrogel Promotes Osteochondral Defect Repair.

The lack of vascular tissue and the low metabolism and biological activity of mature chondrocytes lead to the low regeneration ability of articular cartilage. People try to solve this problem through various methods, but the effect is not very ideal. Inspired by the piezoelectric effect of collagen in cartilage tissue, this work focused on the design of a biomimetic hydrogel by introducing piezoelectric materials and silver nanowires into hydrogel to endow them with piezoelectric and antibacterial properties to promote tissue regeneration. Additionally, the mechanical and swelling properties of the material were adjusted to match natural articular cartilage. Based on bionic principles, a double-layer piezoelectric hydrogel was prepared and applied for the repair of osteochondral defects. An enhanced repair effect of osteochondral defects has been seen, which has demonstrated potential values for future application in bionics principle- and piezoelectric effect-based osteochondral tissue engineering. Furthermore, piezoelectric effect-induced degradation was observed. These results fully indicated the positive effect of the piezoelectric effect on promoting the regeneration of osteochondral tissue and in vivo degradation of materials.

A case of musculi peronaeus tertius anatomic variation.

In the routine dissections study for medical postgraduates, a rare anatomical variation between the right leg and the ankle was observed on the Asian male cadaver. The peronaeus tertius muscle in this cadaver's right leg divided into two tendons: the first tendon was attached to the base of the fifth metatarsal bone, and the second tendon was inserted into the base of the fourth metatarsal bone. The purpose of this paper is to provide detailed anatomical case reports, and to discuss the possible causes and mechanisms of the variation by reviewing relevant literature, so as to provide some reference for future anatomical and clinical related disease research.

Optimal regenerative repair of large segmental bone defect in a goat model with osteoinductive calcium phosphate bioceramic implants.

So far, how to achieve the optimal regenerative repair of large load-bearing bone defects using artificial bone grafts is a huge challenge in clinic. In this study, a strategy of combining osteoinductive biphasic calcium phosphate (BCP) bioceramic scaffolds with intramedullary nail fixation for creating stable osteogenic microenvironment was applied to repair large segmental bone defects (3.0 cm in length) in goat femur model. The material characterization results showed that the BCP scaffold had the initial compressive strength of over 2.0 MPa, and total porosity of 84%. The cell culture experiments demonstrated that the scaffold had the excellent ability to promote the proliferation and osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs). The in vivo results showed that the intramedullary nail fixation maintained the initial stability and structural integrity of the implants at early stage, promoting the osteogenic process both guided and induced by the BCP scaffolds. At 9 months postoperatively, good integration between the implants and host bone was observed, and a large amount of newborn bones formed, accompanying with the degradation of the material. At 18 months postoperatively, almost the complete new bone substitution in the defect area was achieved. The maximum bending strength of the repaired bone defects reached to the 100% of normal femur at 18 months post-surgery. Our results demonstrated the good potential of osteoinductive BCP bioceramics in the regenerative repair of large load-bearing bone defects. The current study could provide an effective method to treat the clinical large segmental bone defects.

Effects of cervical rotatory manipulation on the cervical spinal cord: a finite element study.

BACKGROUND: Little information is available concerning the biomechanism involved in the spinal cord injury after cervical rotatory manipulation (CRM). The primary purpose of this study was to explore the biomechanical and kinematic effects of CRM on a healthy spinal cord. METHODS: A finite element (FE) model of the basilaris cranii, C1-C7 vertebral bodies, nerve root complex and vertebral canal contents was constructed and validated against in vivo and in vitro published data. The FE model simulated CRM in the flexion, extension and neutral positions. The stress distribution, forma and relative position of the spinal cord were observed. RESULTS: Lower von Mises stress was observed on the spinal cord after CRM in the flexion position. The spinal cord in CRM in the flexion and neutral positions had a lower sagittal diameter and cross-sectional area. In addition, the spinal cord was anteriorly positioned after CRM in the flexion position, while the spinal cord was posteriorly positioned after CRM in the extension and neutral positions. CONCLUSION: CRM in the flexion position is less likely to injure the spinal cord, but caution is warranted when posterior vertebral osteophytes or disc herniations exist.

By Endowing Polyglutamic Acid/Polylysine Composite Hydrogel with Super Intrinsic Characteristics to Enhance its Wound Repair Potential.

In this study, multifunctional porous composite hydrogels are prepared via composite technology and using poly(glutamic acid) and (polylysine) as precursors, casein as foaming agent, and calcium ions as coagulant. The results show that the as-prepared hydrogels have high porosity and water absorbency, and good mechanical, inherent antibacterial, and bioadhesive properties. The results show such high water absorption, bioadhesion, and porosity of the as-prepared hydrogel can effectively concentrate blood components and seal wounds better. The release of calcium ions in the as-prepared hydrogels can activate coagulation factors. Both factors can play an important role in hemostasis. The excellent hydroscopicity, moisture retention, adhesion, and inherent antibacterial properties of the as-prepared hydrogel can create a moist, sterile, and closed microenvironment for the wound healing. The experimental results of a deep skin defect model have verified its good effect of promoting wound repair. These inherent excellent properties can endow the as-prepared hydrogel with a wide range of application values.

Joint construction of micro-vibration stimulation and BCP scaffolds for enhanced bioactivity and self-adaptability tissue engineered bone grafts.

The bone defects caused by trauma and disease have become a major difficulty in the treatment of clinical bone defects, and bone tissue engineering has become a promising treatment strategy. It was found that mechanical stimulation regulated the development of bone constructs by affecting the distribution and differentiation of cells on them. In this study, tissue-engineered bone grafts with enhanced bioactivity and self-adaptability were constructed by BMSCs and biphasic calcium phosphate (BCP) scaffolds under periodic micro-vibration stimulation (MVS) with a frequency of 40 Hz and a magnitude of 0.3 g. The results of the material characterization indicated that the BCP scaffolds created a more favourable osteogenic micro-environment with promoted calcium ion release, protein adsorption and mineralization deposition under the micro-vibration stimulation. The in vitro results showed that the apoptosis of BMSCs increased significantly on day 1, but from day 3 on, the proliferation increased and apoptosis decreased. Cells were evenly distributed on the scaffolds, exhibiting tight adhesion in a flat-shape and distinct matrix mineralization. F-actin and ALP expression significantly increased and meanwhile osteogenesis-related genes including Runx2, Col-I, ALP, and OCN were significantly up-regulated. Western blotting results suggested that the ERK1/2 and Wnt/ß-catenin signalling pathways were involved in the osteogenic behaviour of BMSCs induced by MVS. In vivo experiments showed that grafts had stronger osteoinduction and mechanical adaptability. Taken together, this study suggested that micro-vibration stimulation combined with BCP scaffolds with good osteoinduction could be a promising approach for constructing tissue engineered bone grafts with enhanced bioactivity, mechanical adaptability, and bone regeneration repair capability.

Mixed Modification of the Surface Microstructure and Chemical State of Polyetheretherketone to Improve Its Antimicrobial Activity, Hydrophilicity, Cell Adhesion, and Bone Integration.

Polyetheretherketone (PEEK) is becoming an attractive surgical implant material in the biomedical field. However, its hydrophobicity and biological inertia have seriously hindered its development in the field of biomaterials and application in clinic. In this work, a mixed modification approach of the surface structure and chemical state was proposed to improve hydrophilicity and bioactivity of PEEK and meanwhile endowed it with antimicrobial properties. First, the effect of mixed acids of nitric acid and concentrated sulfuric acid with different volume ratios on the surface morphology of PEEK was quantitatively investigated, so as to obtain an optimal mixed acid of nitric acid and concentrated sulfuric acid with a volume ratio that could create a multilevel porous structure. Based on this, chemical grafting of ethylenediamine was conducted to achieve amination on the surface of the PEEK. The results showed that such double modification of the surface structure and chemical state could endow PEEK not only with antimicrobial activity but also with good hydrophilicity, cell compatibility, and bioactivity, which were beneficial to improve the bone integration ability of PEEK greatly.

Constructing Gene-Enhanced Tissue Engineering for Regeneration and Repair of Osteochondral Defects.

In situ sustained release of endogenous growth factors from cells is a challenge for repair and regeneration of tissue. Although recombinant adenovirus vectors are an effective delivery system that can prolong the release of growth factors and is very suitable for the therapy of growth factors, these recombinant adenovirus vectors that are widely used at present have low safety and stability in terms of long-term expression. In this study, the above problems are solved by knocking out both E1 and E3 genes at the same time and directly inserting the gene fragments encoding target proteins after the inverted terminal repeats. Finally, the combination of gene therapy with tissue engineering in regeneration and repair of full-thickness defects of osteochondral tissue are applied as an example. The results show that this strategy can achieve complete repair of articular osteochondral defects and recovery of their function, and meanwhile solve the problems of low safety and expression instability of recombinant adenovirus vectors. This method provides a bright prospect for the application of gene enhanced tissue engineering in the regeneration and repair of joint tissue, and also provides a reference for the repair and regeneration of other tissues.

A strategy using mesoporous polymer nanospheres as nanocarriers of Bcl-2 siRNA towards breast cancer therapy.

Small interference RNA (siRNA) has demonstrated unprecedented potential as a therapy for drug-resistant cancer. However, efficient cellular delivery is still a challenge due to hydrolytic sensitivity and poor cellular uptake of siRNA. Strategies to conjugate siRNA to the delivery vehicle and activate innate immunity have shown low in vivo efficacy. Therefore, nanomedicine approaches have become the main focus in this field. B-cell lymphoma 2 (Bcl-2) is the founding member of the Bcl-2 family of regulatory proteins that regulate cell death (apoptosis), by either inducing (pro-apoptotic) or inhibiting (anti-apoptotic) apoptosis. In this report, a nanomedicine system is constructed using Bcl-2 siRNA as the therapeutic agent and mesoporous polymer nanosphere (MPN) carriers to both improve cellular internalization and achieve Bcl-2 silencing and cell apoptosis. MPNs were prepared through a two-stage hydrothermal process at two different temperatures, which was deliberately designed to form nanospheres via self-assembly and create mesoporous structures by removing the pore-forming templates. Such MPNs were proved to be biodegradable. Without any carbonization process, MPNs still keep many active groups which endow them with excellent properties for functionalization purposes. Finally, the FA-targeted-Bcl-2-siRNA-loaded nanoparticles were constructed by a layer-by-layer assembly by electrostatic interactions after nitrification. These nanoparticles were efficiently delivered into breast cancer (BC) cells, showing a significant sequence-specific inhibition of Bcl-2 mRNA expression in BC cells, enhanced tumor cell apoptosis and tumor therapeutic efficacy. Taken together, this study establishes a novel therapeutic system for cancer therapy.

A single integrated osteochondral in situ composite scaffold with a multi-layered functional structure.

This work focuses on the optimization design of a functional biomimetic scaffold for the repair of osteochondral defects and includes the study of single integrated osteochondral tissue engineering scaffolds with a multi-layered functional structure. Rabbit model experiments were used to evaluate the repair of osteochondral defects. The results revealed that good integration was achieved both at the interfaces between the scaffold material and the host tissue and between the newly formed subchondral bone and cartilage. The highest total histological score of 24.2 (based on the modified O'Driscoll scoring system at 12 weeks post-operation) was achieved for osteochondral repair. The completely repaired cylindrical full-thickness defects for the rabbit animal model reached 5 mm in diameter. The thickness of the regenerated cartilage was almost in line with that of the surrounding normal cartilage, the number and arrangement of cells in the superficial area of cartilage were very close to those of normal hyaline cartilage, and there were clear cartilage lacunas in the regenerated cartilage. The hybrid-use of growth factors and LIPUS stimulation exhibited good potential in enhancing vascularization and the formation of new bone and cartilage, providing better conditions for the overall osteochondral repair.

Biomimetic Bacterial Cellulose-Enhanced Double-Network Hydrogel with Excellent Mechanical Properties Applied for the Osteochondral Defect Repair.

Although hydrogels based on biopolymers show many advantages, their low mechanical properties limit their applications in osteochondral tissue engineering. In this study, one part of our work aimed at preparing a high strength biohydrogel by using a double-network (DN) hydrogel system, which consisted of two interpenetrating polymer networks composed of γ-glutamic acid, lysine, and alginate, and meanwhile by incorporating bacterial cellulose into the DN structures. The results showed that compression modulus of the resultant hydrogel (0.322 MPa) was comparable with that of natural articular cartilage and swelling degree was greatly depressed by using these strategies. On this basis, a bilayer hydrogel scaffold based on the bionics principle for osteochondral regeneration was fabricated via chemical and physical cross-linking. Additionally, hydroxyapatite (HA) particles with two different sizes were introduced into the bilayer hydrogels, respectively: micro-HA in the top layer for promoting cartilage matrix deposition and HA nanocrystals in the bottom layer for enhancing compression modulus and osteogenesis. The osteochondral defect model of rabbits was used to evaluate the repair effect of the scaffolds with the bilayer structure, and the results showed such as-synthesized scaffolds had a good osteochondral repair effect.

Hybrid use of combined and sequential delivery of growth factors and ultrasound stimulation in porous multilayer composite scaffolds to promote both vascularization and bone formation in bone tissue engineering.

In this study, a multilayer coating technology would be adopted to prepare a porous composite scaffold and the growth factor release and ultrasound techniques were introduced into bone tissue engineering to finally solve the problems of vascularization and bone formation in the scaffold whilst the designed multilayer composite with gradient degradation characteristics in the space was used to match the new bone growth process better. The results of animal experiments showed that the use of low intensity pulsed ultrasound (LIPUS) combined with growth factors demonstrated excellent capabilities and advantages in both vascularization and new bone formation in bone tissue engineering. The degradation of the used scaffold materials could match new bone formation very well. The results also showed that only RGD-promoted cell adhesion was insufficient to satisfy the needs of new bone formation while growth factors and LIPUS stimulation were the key factors in new bone formation.

Porous nanoapatite scaffolds synthesized using an approach of interfacial mineralization reaction and their bioactivity.

There is a growing interest in the use of calcium phosphate, used to fabricate porous scaffolds for bone tissue regeneration and repair. However, it is difficult to obtain interconnected pores with very high porosity and to engineer the topography of the pore walls for calcium phosphate ceramic scaffolds. In this study, a novelty method interfacial mineralization reaction was used to fabricate porous nano-calcium phosphate ceramic scaffolds with three-dimensional surface topography of walls, which was tuned using different surfactants; using this method, porous scaffolds with different shapes were obtained, which demonstrates that interfacial mineralization reaction is not only a good method to prepare porous ceramic scaffolds of calcium phosphate but also an efficient approach to engineer the topography of the pore walls. The as-prepared porous ceramic scaffolds have also been proved to have good biocompatibility, bioactivity, and biodegradability, which are necessary for the clinical application. In vivo experimental results revealed that not only osteoconduction but also osteoinduction was responsible for the bone formation in our scaffolds, which accelerated the formation of new bone, and that the degradation process of our porous scaffolds could match osteoinduction, mineralization of matrix and bone, and reconstruction of new bone very well, and porous scaffolds could be completely substituted by the new bone.