Endogenous Electric Field-Coupled PD@BP Biomimetic Periosteum Promotes Bone Regeneration through Sensory Nerve via Fanconi Anemia Signaling Pathway.

To treat bone defects, repairing the nerve-rich periosteum is critical for repairing the local electric field. In this study, an endogenous electric field is coupled with 2D black phosphorus electroactive periosteum to explore its role in promoting bone regeneration through nerves. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) are used to characterize the electrically active biomimetic periosteum. Here, the in vitro effects exerted by the electrically active periosteum on the transformation of Schwann cells into the repair phenotype, axon initial segment (AIS) and dense core vesicle (DCV) of sensory neurons, and bone marrow mesenchymal stem cells are assessed using SEM, immunofluorescence, RNA-sequencing, and calcium ion probes. The electrically active periosteum stimulates Schwann cells into a neuroprotective phenotype via the Fanconi anemia pathway, enhances the AIS effect of sensory neurons, regulates DCV transport, and releases neurotransmitters, promoting the osteogenic transformation of bone marrow mesenchymal stem cells. Microcomputed tomography and other in vivo techniques are used to study the effects of the electrically active periosteum on bone regeneration. The results show that the electrically active periosteum promotes nerve-induced osteogenic repair, providing a potential clinical strategy for bone regeneration.

Photosensitive and Conductive Hydrogel Induced Innerved Bone Regeneration for Infected Bone Defect Repair.

Repairing infected bone defects is a challenge in the field of orthopedics because of the limited self-healing capacity of bone tissue and the susceptibility of refractory materials to bacterial activity. Innervation is the initiating factor for bone regeneration and plays a key regulatory role in subsequent vascularization, ossification, and mineralization processes. Infection leads to necrosis of local nerve fibers, impeding the repair of infected bone defects. Herein, a biomaterial that can induce skeletal-associated neural network reconstruction and bone regeneration with high antibacterial activity is proposed for the treatment of infected bone defects. A photosensitive conductive hydrogel is prepared by incorporating magnesium-modified black phosphorus (BP@Mg) into gelatin methacrylate (GelMA). The near-infrared irradiation-based photothermal and photodynamic treatment of black phosphorus endows it with strong antibacterial activity, improving the inflammatory microenvironment and reducing bacteria-induced bone tissue damage. The conductive nanosheets and bioactive ions released from BP@Mg synergistically improve the migration and secretion of Schwann cells, promote neurite outgrowth, and facilitate innerved bone regeneration. In an infected skull defect model, the GelMA-BP@Mg hydrogel shows efficient antibacterial activity and promotes bone and CGRP+ nerve fiber regeneration. The phototherapy conductive hydrogel provides a novel strategy based on skeletal-associated innervation for infected bone defect repair.

The Application of Black Phosphorus Nanomaterials in Bone Tissue Engineering.

Recently, research on and the application of nanomaterials such as graphene, carbon nanotubes, and metal-organic frameworks has become increasingly popular in tissue engineering. In 2014, a two-dimensional sheet of black phosphorus (BP) was isolated from massive BP crystals. Since then, BP has attracted significant attention as an emerging nanomaterial. BP possesses many advantages such as light responsiveness, electrical conductivity, degradability, and good biocompatibility. Thus, it has broad prospects in biomedical applications. Moreover, BP is composed of phosphorus, which is a key bone tissue component with good biocompatibility and osteogenic repair ability. Thereby, BP exhibits excellent advantages for application in bone tissue engineering. In this review, the structure and the physical and chemical properties of BP are described. In addition, the current applications of BP in bone tissue engineering are reviewed to aid the future research and application of BP.

Recent Advances in the Application of Natural and Synthetic Polymer-Based Scaffolds in Musculoskeletal Regeneration.

The musculoskeletal system plays a critical role in providing the physical scaffold and movement to the mammalian body. Musculoskeletal disorders severely affect mobility and quality of life and pose a heavy burden to society. This new field of musculoskeletal tissue engineering has great potential as an alternative approach to treating large musculoskeletal defects. Natural and synthetic polymers are widely used in musculoskeletal tissue engineering owing to their good biocompatibility and biodegradability. Even more promising is the use of natural and synthetic polymer composites, as well as the combination of polymers and inorganic materials, to repair musculoskeletal tissue. Therefore, this review summarizes the progress of polymer-based scaffolds for applications of musculoskeletal tissue engineering and briefly discusses the challenges and future perspectives.

Small Intestinal Submucosa Biomimetic Periosteum Promotes Bone Regeneration.

BACKGROUND: Critical bone defects are a significant problem in clinics. The periosteum plays a vital role in bone regeneration. A tissue-engineered periosteum (TEP) has received increasing attention as a novel strategy for bone defect repairs. METHODS: In this experiment, a biomimetic periosteum was fabricated by using coaxial electrospinning technology with decellularized porcine small intestinal submucosa (SIS) as the shell and polycaprolactone (PCL) as the core. In vitro, the effects of the biomimetic periosteum on Schwann cells, vascular endothelial cells, and bone marrow mesenchymal stem cells were detected by a scratch test, an EdU, a tube-forming test, and an osteogenesis test. In vivo, we used HE staining to evaluate the effect of the biomimetic periosteum on bone regeneration. RESULTS: In vitro experiments showed that the biomimetic periosteum could significantly promote the formation of angiogenesis, osteogenesis, and repaired Schwann cells (SCs). In vivo experiments showed that the biomimetic periosteum could promote the repair of bone defects. CONCLUSIONS: The biomimetic periosteum could simulate the structural function of the periosteum and promote bone repair. This strategy may provide a promising method for the clinical treatment of skull bone defects.

Multifunctional hydrogel loaded with 4-octyl itaconate exerts antibacterial, antioxidant and angiogenic properties for diabetic wound repair.

Cutaneous wound healing, especially diabetic wound healing, is a common clinical problem. Reactive oxygen species (ROS) and bacterial infection are two major factors in the induction of oxidative stress and inflammation, leading to impeded angiogenesis and wound healing. However, it is still very difficult to reverse the harsh microenvironment of chronic inflammation and excessive oxidative stress on diabetic wound. Itaconate, an endogenous metabolite, has recently attracted extensive attention as a critical immune-regulator. In this study, we used 4-octyl itaconate (4OI), a cell-permeable itaconate derivative, to have antioxidative and anti-inflammatory functions for diabetic wound regeneration. Simultaneously, an injectable, self-healing, and antibacterial dynamic coordinative hydrogel was manufactured by binding the 4-arm polyethylene glycol (PEG) with silver nitrate to deliver the bioactive molecule. In vitro experiments confirmed that 4OI@PEG hydrogel could inhibit bacterial growth, protect human umbilical vein endothelial cells from ROS damage and enhance neovascularization. In addition, the hydrogel increased mitochondrial polarization and reduced mitochondrial fragmentation by activating the Keap1-Nrf2 antioxidant defense system. In vivo experiments proved that this multifunctional hydrogel facilitated diabetic wound healing by inhibiting local inflammation and promoting angiogenesis. Collectively, 4OI-loaded multifunctional materials could reverse various unfavorable microenvironments, such as excessive oxidative stress, inflammation, and infection, and can promote neovascularization; thus, such materials show great promise for the treatment of diabetic ulcers.

Bioinspired Multifunctional Black Phosphorus Hydrogel with Antibacterial and Antioxidant Properties: A Stepwise Countermeasure for Diabetic Skin Wound Healing.

Cutaneous wound healing, especially diabetic wound healing, is a common clinical challenge. Reactive oxygen species (ROS) and bacterial infection are two major detrimental states that induce oxidative stress and inflammatory responses and impede angiogenesis and wound healing. A derivative of the metabolite itaconate, 4-octyl itaconate (4OI) has attracted increasing research interest in recent years due to its antioxidant and anti-inflammatory properties. In this study, 4OI-modified black phosphorus (BP) nanosheets are incorporated into a photosensitive, multifunctional gelatin methacrylamide hydrogel to produce a new photothermal therapy (PTT) and photodynamic therapy (PDT) system with antibacterial and antioxidant properties for diabetic wound regeneration. Under laser irradiation, the 4OI-BP-entrapped hydrogel enables rapid gelation, forming a membrane on wounds, and offers high PTT and PDT efficacy to eliminate bacterial infection. Without laser irradiation, BP acts as a carrier and controls the release of 4OI, with which it synergistically enhances antioxidant activity, thus alleviating excessive ROS damage to endothelial cells, promoting neovascularization, and facilitating faster diabetic wound closure. These findings indicate that 4OI-BP-entrapped multifunctional hydrogel provides a stepwise countermeasure with antibacterial and antioxidant properties for enhanced diabetic wound healing and may lead to novel therapeutic interventions for diabetic ulcers.

Treatment of Upper Cervical Spinal Cord Injury (Unstable C1-C2) by Direct Visualization and Nailing Technique and the Advantages of Early MRI.

Background: The treatment of C1-C2 fractures mainly depends on fracture type and the stability of the atlantoaxial joint. Disruption of the C1-C2 combination is a big challenge, especially in avoiding vertebral artery, nerve, and vein sinus injury during the operation. Purpose: This study aims to show the benefit of using the posterior approach and pedicle screw insertion by nailing technique and direct visualization to treat unstable C1-C2 and, moreover, to determine the advantages of performing early MRI in patients with limited neck movement after trauma. Method: Between Jan 2017-Feb 2019, we present 21 trauma patients who suffered from C1, C2, or unstable atlantoaxial joint. X-ray, computed tomography (CT), and magnetic resonance image (MRI) were performed preoperatively. All the patients underwent our surgical procedure (posterior approach and pedicle screw placement by direct visualization and nailing technique). Result: The mean age was 41.1 years old, 8 females and 14 males. The average follow-up time was 2.6 years. Four patients were with C1 fracture, seven with C2 fracture, six with atlantoaxial dislocation, and four with C1 and C2 fractures. The time of MRI was between 12 hours and 48 hours; neck movement symptoms appeared between 2 days and 2 weeks. Conclusion: The posterior approach to treat the C1 and C2 fractures or dislocation by direct visualization and nailing technique can reduce the risk of the vertebral artery, vein sinus, and nerve root injuries with significant improvement. It can show a better angle view while inserting the pedicle screws. An early MRI (12-48 hours) is essential even if no symptoms appear at the time of admission, and if it is normal, it is necessary to repeat it. The presence of skull bleeding can be associated with upper neck instability.

Medical Communication Services after Traumatic Spinal Cord Injury.

It is difficult to assess and monitor the spinal cord injury (SCI) because of its pathophysiology after injury, with different degrees of prognosis and various treatment methods, including laminectomy, durotomy, and myelotomy. Medical communication services with different factors such as time of surgical intervention, procedure choice, spinal cord perfusion pressure (SCPP), and intraspinal pressure (ISP) contribute a significant role in improving neurological outcomes. This review aims to show the benefits of communication services and factors such as ISP, SCPP, and surgical intervention time in order to achieve positive long-term outcomes after an appropriate treatment method in SCI patients. The SCPP was found between 90 and 100 mmHg for the best outcome, MAP was found between 110 and 130 mmHg, and mean ISP is ≤20 mmHg after injury. Laminectomy alone cannot reduce the pressure between the dura and swollen cord. Durotomy and duroplasty considered as treatment choices after severe traumatic spinal cord injury (TSCI).

Controlled delivery of bone morphogenic protein-2-related peptide from mineralised extracellular matrix-based scaffold induces bone regeneration.

Ideal bone tissue engineering scaffolds composed of extracellular matrix (ECM) require excellent osteoconductive ability to imitate the bone environment. We developed a mineralised tissue-derived ECM-modified true bone ceramic (TBC) scaffold for the delivery of aspartic acid-modified bone morphogenic protein-2 (BMP-2) peptide (P28) and assessed its osteogenic capacity. Decellularized ECM from porcine small intestinal submucosa (SIS) was coated onto the surface of TBC, followed by mineralisation modification (mSIS/TBC). P28 was subsequently immobilised onto the scaffolds in the absence of a crosslinker. The alkaline phosphatase activity and other osteogenic differentiation marker results showed that osteogenesis of the P28/mSIS/TBC scaffolds was significantly greater than that of the TBC and mSIS/TBC groups. In addition, to examine the osteoconductive capability of this system in vivo, we established a rat calvarial bone defect model and evaluated the new bone area and new blood vessel density. Histological observation showed that P28/mSIS/TBC exhibited favourable bone regeneration efficacy. This study proposes the use of mSIS/TBC loaded with P28 as a promising osteogenic scaffold for bone tissue engineering applications.

In situ bone regeneration with sequential delivery of aptamer and BMP2 from an ECM-based scaffold fabricated by cryogenic free-form extrusion.

In situ tissue engineering is a powerful strategy for the treatment of bone defects. It could overcome the limitations of traditional bone tissue engineering, which typically involves extensive cell expansion steps, low cell survival rates upon transplantation, and a risk of immuno-rejection. Here, a porous scaffold polycaprolactone (PCL)/decellularized small intestine submucosa (SIS) was fabricated via cryogenic free-form extrusion, followed by surface modification with aptamer and PlGF-2123-144*-fused BMP2 (pBMP2). The two bioactive molecules were delivered sequentially. The aptamer Apt19s, which exhibited binding affinity to bone marrow-derived mesenchymal stem cells (BMSCs), was quickly released, facilitating the mobilization and recruitment of host BMSCs. BMP2 fused with a PlGF-2123-144 peptide, which showed "super-affinity" to the ECM matrix, was released in a slow and sustained manner, inducing BMSC osteogenic differentiation. In vitro results showed that the sequential release of PCL/SIS-pBMP2-Apt19s promoted cell migration, proliferation, alkaline phosphatase activity, and mRNA expression of osteogenesis-related genes. The in vivo results demonstrated that the sequential release system of PCL/SIS-pBMP2-Apt19s evidently increased bone formation in rat calvarial critical-sized defects compared to the sequential release system of PCL/SIS-BMP2-Apt19s. Thus, the novel delivery system shows potential as an ideal alternative for achieving cell-free scaffold-based bone regeneration in situ.

Treatment of anterior column posterior hemitransverse fracture with supra-ilioinguinal approach.

OBJECTIVE: To report the feasibility and effect of the supra-ilioinguinal approach for treatment of anterior posterior hemitransverse fracture of the acetabulum. METHODS: Nineteen consecutive patients who underwent treatment for an anterior column posterior hemitransverse fracture of the acetabulum from January 2013 to June 2018 were retrospectively analyzed. All patients underwent treatment by the single supra-ilioinguinal approach with at least 1 year of follow-up. RESULTS: The mean time to surgery, operative time, incision length, and blood loss were 10.2 ± 3.8 days, 157 ± 125 minutes, 10.2 ± 0.6 cm, and 876 ± 234 mL, respectively. According to the Matta scoring system, the reduction quality was excellent in 13 patients, good in 6, and poor in 0. According to the Merle d'Aubigné scoring system, the outcome at the last follow-up was excellent in 12 patients, good in 5, fair in 1, and poor in 1. Postoperative complications occurred in three patients (deep vein thrombosis in one, lateral femoral cutaneous nerve injury in one, and both complications in one). CONCLUSIONS: Use of the supra-ilioinguinal approach for treatment of anterior column posterior hemitransverse fracture of the acetabulum produced excellent clinical results because of the direct visualization of the anterior column and quadrilateral plate.

Magnesium-based materials in orthopaedics: material properties and animal models.

As a new generation of medical metal materials, degradable magnesium-based materials have excellent mechanical properties and osteogenic promoting ability, making them promising materials for the treatment of refractory bone diseases. Animal models can be used to understand and evaluate the performance of materials in complex physiological environments, providing relevant data for preclinical evaluation of implants and laying the foundation for subsequent clinical studies. To date, many researchers have studied the biocompatibility, degradability and osteogenesis of magnesium-based materials, but there is a lack of review regarding the effects of magnesium-based materials in vivo. In view of the growing interest in these materials, this review briefly describes the properties of magnesium-based materials and focuses on the safety and efficacy of magnesium-based materials in vivo. Various animal models including rats, rabbits, dogs and pigs are covered to better understand and evaluate the progress and future of magnesium-based materials. This literature analysis reveals that the magnesium-based materials have good biocompatibility and osteogenic activity, thus causing no adverse reaction around the implants in vivo, and that they exhibit a beneficial effect in the process of bone repair. In addition, the degradation rate in vivo can also be improved by means of alloying and coating. These encouraging results show a promising future for the use of magnesium-based materials in musculoskeletal disorders.

Surface modified small intestinal submucosa membrane manipulates sequential immunomodulation coupled with enhanced angio- and osteogenesis towards ameliorative guided bone regeneration.

Constructing bioactive guided bone regeneration (GBR) membranes that possess biological multifunctionality is becoming increasingly attractive and promising to meet higher requirements for bone healing. Given the biological responses following implantation, GBR process originates from an early inflammation-driven reaction adjacent to implanted membranes surface. However, to date there is relatively little attention paid to the critical immunoregulatory functions in traditionally designed GBR membranes. Herein, for the first time, we manipulate immunomodulatory properties of the widely-used native small intestinal submucosa (SIS) membrane by incorporating strontium-substituted nanohydroxyapatite coatings and/or IFN-γ to its surface. In vitro results reveal the obtained novel membrane SIS/SrHA/IFN-γ not only promote functions of endothelial cells and osteoblasts directly, but also energetically mediate a sequential M1-M2 macrophages transition to concurrently facilitate angiogenesis and osteogenesis. Moreover, in vivo outcomes of subcutaneous implantation and cranial defects repair further confirm its superior capacity to promote vascularization and in situ bone regeneration than pristine SIS through immunomodulation. These results demonstrate a sequential immunomodulatory strategy renders modified SIS membranes acting as a robust immunomodulator rather than a traditional barrier to significantly ameliorate in vivo GBR outcomes and hence provide important implications that may facilitate concerns on immunomodulatory properties for future GBR developments.

Bioactive Sr2+/Fe3+co-substituted hydroxyapatite in cryogenically 3D printed porous scaffolds for bone tissue engineering.

Developing multi-doped bioceramics that possess biological multifunctionality is becoming increasingly attractive and promising for bone tissue engineering. In this view innovative Sr2+/Fe3+co-substituted nano-hydroxyapatite with gradient doping concentrations fixed at 10 mol% has been deliberately designed previously. Herein, to evaluate their therapeutic potentials for bone healing, novel gradient SrFeHA/PCL scaffolds are fabricated by extrusion cryogenic 3D printing technology with subsequent lyophilization. The obtained scaffolds exhibit desired 3D interconnected porous structure and rough microsurface, along with appreciable release of bioactive Sr2+/Fe3+from SrFeHA components. These favorable physicochemical properties render printed scaffolds realizing effective biological applications bothin vitroandin vivo, particularly the moderate co-substituted Sr7.5Fe2.5HA and Sr5Fe5HA groups exhibit remarkably enhanced bioactivity that not only promotes the functions of MC3T3 osteoblasts and HUVECs directly, but also energetically manipulates favorable macrophages activation to concurrently facilitate osteogenesis/angiogenesis. Moreover,in vivosubcutaneous implantation and cranial defects repair outcomes further confirm their superior capacity to dictate immune reaction, implants vascularization andin situbone regeneration, mainly dependent on the synergetic effects of released Sr2+/Fe3+. Accordingly, for the first time, present study highlights the great potential of Sr7.5Fe2.5HA and Sr5Fe5HA for ameliorating bone regeneration process by coupling of immunomodulation with enhanced angio- and osteogenesis and hence may provide a new promising alternative for future bone tissue engineering.

Creation of Bony Microenvironment with Extracellular Matrix Doped-Bioactive Ceramics to Enhance Osteoblast Behavior and Delivery of Aspartic Acid-Modified BMP-2 Peptides.

INTRODUCTION: Decellularized matrix from porcine small intestinal submucosa (SIS) endows scaffolds with an ECM-like surface, which enhances stem cell self-renewal, proliferation, and differentiation. Mesoporous bioactive glass (MBG) is extensively recognized as an excellent bio-ceramic for fabricating bone grafts. MATERIALS AND METHODS: In the current study, SIS was doped on an MBG scaffold (MBG/SIS) using polyurethane foam templating and polydopamine chemistry method. To mimic the bony environment of a natural bone matrix, an ECM-inspired delivery system was constructed by coupling the BMP2-related peptide P28 to a heparinized MBG/SIS scaffold (MBG/SIS-H-P28). The release of P28 from MBG/SIS-H-P28 and its effects on the proliferation, viability, and osteogenic differentiation of bone marrow stromal stem cells were investigated in vitro and in vivo. RESULTS: Our research indicated that the novel tissue-derived ECM scaffold MBG/SIS has a hierarchical and interconnected porous architecture, and superior biomechanical properties. MBG/SIS-H-P28 released P28 in a controlled manner, with the long-term release time of 40 d. The results of in vitro experiments showed improvements in cell proliferation, cell viability, alkaline phosphatase activity, and mRNA expression levels of osteogenesis-related genes (Runx-2, OCN, OPN, and ALP) compared to those of MBG/SIS or MBG/SIS-P28 and MBG/SIS-H-P28. The in vivo results demonstrated that MBG/SIS-H-P28 scaffolds evidently increased bone formation in rat calvarial critical-sized defect compared to that in controls. CONCLUSION: MBG/SIS-H-P28 scaffolds show potential as ideal platforms for delivery of P28 and for providing a bony environment for bone regeneration.

Biomechanical Comparison of Different Fixation Techniques for Typical Acetabular Fractures in the Elderly: The Role of Special Quadrilateral Surface Buttress Plates.

BACKGROUND: Anterior column-posterior hemitransverse fractures are prevalent in the elderly and are often associated with quadrilateral surface (QLS) comminution. Several special QLS buttress plates have been introduced, but evidence of their comparability with traditional fixation devices is lacking. This biomechanical study aimed to compare special QLS buttress plates with traditional fixation devices. METHODS: Anterior column-posterior hemitransverse fractures with an isolated QLS fragment were created on 24 composite hemipelves and were allocated to 4 fixation groups: (1) infrapectineal QLS buttress plate, (2) suprapectineal QLS buttress plate, (3) suprapectineal reconstruction plate with 3 periarticular long screws, and (4) infrapectineal reconstruction plate with 3 periarticular long screws. Specimens were loaded to simulate partial weight-bearing (35 to 350 N) or full weight-bearing (75 to 750 N). A testing machine was synchronized with a 3-dimensional video tracking system to optically track displacement at the points of interest and to calculate construct stiffness. The fixation systems were compared using the Kruskal-Wallis and Mann-Whitney U tests. RESULTS: The experimental results of the partial and full weight-bearing simulations were surprisingly similar. During 40 loading cycles, the maximum displacement on the 6 predetermined points did not exceed 1.1 mm. Multiple-group comparisons of relative displacements of each predetermined measurement point did not differ significantly (p > 0.05). The suprapectineal reconstruction plate with 3 periarticular long screws demonstrated the greatest construct stiffness and significantly greater stiffness than the infrapectineal plate with long screws (p < 0.017). However, no significant difference (p > 0.017) in stiffness was identified between the infrapectineal QLS buttress plate and the suprapectineal reconstruction plate with long screws. CONCLUSIONS: The suprapectineal pelvic brim plate with 3 periarticular long screws remains the gold standard to treat anterior column-posterior hemitransverse fractures. The special infrapectineal QLS buttress plate provides stiffness and stability comparable with those of standard fixation. However, moving the pelvic brim plate from the suprapectineal border to the infrapectineal border is not recommended for anterior column-posterior hemitransverse fractures because it significantly decreases fixation stiffness. CLINICAL RELEVANCE: Special QLS buttress plates may be an alternative fixation method for anterior column-posterior hemitransverse acetabular fractures in the elderly, especially when a less invasive anterior intrapelvic approach is selected.