Magnetic Seeding of SPIO-BMSCs Into a Biphasic Scaffold Can Promote Tendon-Bone Healing After Rotator Cuff Repair.

BACKGROUND: The tendon-bone interface (TBI) in the rotator cuff has a poor intrinsic capacity for healing, which increases the risk of retear after rotator cuff repair (RCR). However, facilitating regeneration of the TBI still remains a great clinical challenge. Herein, the authors established a novel strategy based on magnetic seeding to enhance the TBI regeneration. HYPOTHESIS: Magnetic seeding bone marrow mesenchymal stem cells labeled with superparamagnetic iron oxide (SPIO-BMSCs) into a biphasic scaffold can promote tendon-bone healing after RCR. STUDY DESIGN: Controlled laboratory study. METHODS: BMSCs were labeled with SPIOs. Prussian blue staining, CCK-8 tests, Western blot, and quantitative reverse transcription polymerase chain reaction (PCR) were used to determine the optimal effect concentration of SPIOs on cell bioactivities and abilities. Then SPIO-BMSCs were magnetically seeded into a biphasic scaffold under a magnetic field. The seeding efficacy was assessed by a scanning electron microscope, and the potential mechanism in chondrogenic differentiation after seeding SPIO-BMSCs into the scaffold was evaluated by Western blot and PCR. Furthermore, the effect of SPIO-BMSC/biphasic scaffold on tendon-bone healing after RCR using a rat model was examined using histological analysis, enzyme-linked immunosorbent assay, and biomechanical evaluation. RESULTS: BMSCs labeled with 100 µg/mL SPIO had no effect on cell bioactivities and the ability of chondrogenic differentiation. SPIO-BMSCs were magnetically seeded into a biphasic scaffold, which offered a high seeding efficacy to enhance chondrogenic differentiation of SPIO-BMSCs via the CDR1as/miR-7/FGF2 pathway for TBI formation in vitro. Furthermore, in vivo application of the biphasic scaffold with magnetically seeded SPIO-BMSCs showed their regenerative potential, indicating that they could significantly accelerate and promote TBI healing with superior biomechanical properties after RCR in a rat rotator cuff tear model. CONCLUSION: Magnetically seeding SPIO-BMSCs into a biphasic scaffold enhanced seeding efficacy to promote cell distribution and condensation. This construct enhanced the chondrogenesis process via the CDR1as/miR-7/FGF2 pathway and further promoted tendon-bone healing after RCR in a rat rotator cuff tear model. CLINICAL RELEVANCE: This study provides an alternative strategy for improving TBI healing after RCR.

Carbomer Hydrogel Composed of Cu2O and Hematoporphyrin Monomethyl Ether Promotes the Healing of Infected Wounds.

Infectious wounds pose a significant challenge in the field of wound healing primarily due to persistent inflammation and the emergence of antibiotic-resistant bacteria. To combat these issues, the development of an effective wound dressing that can prevent infection and promote healing is of the utmost importance. Photodynamic therapy (PDT) has emerged as a promising noninvasive treatment strategy for tackling antibiotic-resistant bacteria. A biodegradable photosensitizer called hematoporphyrin monomethyl ether (HMME) has shown potential in generating reactive oxygen species (ROS) upon laser activation to combat bacteria. However, the insolubility of HMME limits its antibacterial efficacy and its ability to facilitate skin healing. To overcome these limitations, we have synthesized a compound hydrogel by combining carbomer, HMME, and Cu2O nanoparticles. This compound hydrogel exhibits enhanced antimicrobial ability and excellent biocompatibility and promotes angiogenesis, which is crucial for the healing of skin defects. By integrating the benefits of HMME, Cu2O nanoparticles, and the gel-forming properties of carbomer, this compound hydrogel shows great potential as an effective wound dressing material. In summary, the compound hydrogel developed in this study offers a promising solution for infectious wounds by addressing the challenges of infection prevention and promoting skin healing. This innovative approach utilizing PDT and the unique properties of the compound hydrogel could significantly improve the outcomes of wound healing in clinical settings.

Mechanochemically Reprogrammed Interface Orchestrates Neutrophil Bactericidal Activity and Apoptosis for Preventing Implant-Associated Infection.

The onset of implant-associated infection (IAI) triggers a cascade of immune responses, which are initially dominated by neutrophils. Bacterial aggregate formation and hypoxic microenvironment, which occur shortly after implantation, may be two major risk factors that impair neutrophil function and lead to IAI. Here, the implant surface with phytic acid-Zn2+ coordinated TiO2 nanopillar arrays (PA-Zn@TiNPs) and oxygen self-supporting CaO2 nanoparticles, named as CPZTs, is mechanochemically reprogrammed. The engineered CPZTs interface integrates multiple properties to inhibit the formation of nascent biofilm, encompassing antibacterial adhesion, mechanobactericidal effect, and chemobiocidal effect. Meanwhile, continuous oxygenation fuels the neutrophils with reactive oxygen species (ROS) for efficient bacterial elimination on the implant surface and inside the neutrophils. Furthermore, this surface modulation strategy accelerates neutrophil apoptosis and promotes M2 macrophage-mediated osteogenesis both in vitro and in a rat model of IAI. In conclusion, targeting neutrophils for immunomodulation is a practical and effective strategy to prevent IAI and promote bone-implant integration.

Biphasic release of betamethasone from an injectable HA hydrogel implant for alleviating lumbar disc herniation induced sciatica.

Epidural steroid injection (ESI) is a common therapeutic approach for managing sciatica caused by lumbar disc herniation (LDH). However, the short duration of therapeutic efficacy and the need for repeated injections pose challenges in LDH treatment. The development of a controlled delivery system capable of prolonging the effectiveness of ESI and reducing the frequency of injections, is highly significant in LDH clinical practice. In this study, we utilized a thiol-ene click chemistry to create a series of injectable hyaluronic acid (HA) based release systems loaded with diphasic betamethasone, including betamethasone dipropionate (BD) and betamethasone 21-phosphate disodium (BP) (BD/BP@HA). BD/BP@HA hydrogel implants demonstrated biocompatibility and biodegradability to matched neuronal tissues, avoiding artificial compression following injection. The sustained release of betamethasone from BD/BP@HA hydrogels effectively inhibited both acute and chronic neuroinflammation by suppressing the nuclear factor kappa-B (NF-κB) pathway. In a mouse model of LDH, the epidural administration of BD/BP@HA efficiently alleviated LDH-induced sciatica for at least 10 days by inhibiting the activation of macrophages and microglia in dorsal root ganglion and spinal dorsal horn, respectively. The newly developed HA hydrogels represent a valuable platform for achieving sustained drug release. Additionally, we provide a simple paradigm for fabricating BD/BP@HA for epidural injection, demonstrating greater and sustained efficiency in alleviating LDH-induced sciatica compared to traditional ESI and displaying potentials for clinical translation. This system has the potential to revolutionize drug delivery for co-delivery of both soluble and insoluble drugs, thereby making a significant impact in the pharmaceutical industry. STATEMENT OF SIGNIFICANCE: Lumbar disc herniation (LDH) is a common degenerative disorder leading to sciatica and spine surgery. Although epidural steroid injection (ESI) is routinely used to alleviate sciatica, the efficacy is short and repeated injections are required. There remains challenging to prolong the efficacy of ESI. Herein, an injectable hyaluronic acid (HA) hydrogel implant by crosslinking acrylated-modified HA (HA-A) with thiol-modified HA (HA-SH) was designed to achieve a biphasic release of betamethasone. The hydrogel showed biocompatibility and biodegradability to match neuronal tissues. Notably, compared to traditional ESI, the hydrogel better alleviated sciatica in vivo by synergistically inhibiting the neuroinflammation in central and peripheral nervous systems. We anticipate the injectable HA hydrogel implant has the potential for clinical translation in treating LDH-induced sciatica.

Cartilage fragments combined with BMSCs-Derived exosomes can promote tendon-bone healing after ACL reconstruction.

Anterior cruciate ligament reconstruction (ACLR) often fails due to the inability of tendon-bone integration to regenerate normal tissues and formation of fibrous scar tissues in the tendon-bone interface. Cartilage fragments and exosomes derived from bone mesenchymal stromal cells (BMSCs-Exos) can enhance enthesis healing. Nevertheless, the effects on the tendon-bone healing of ACLR remain unknown. This study found that BMSCs-Exos can promote the proliferation of chondrocytes in cartilage fragments, and activated the expression of chondro-related genes SOX9 and Aggrecan. The optimal effect concentration was 1012 events/uL. Besides, BMSCs-Exos could significantly upregulated the expression of BMP7 and Smad5 in cartilage fragments, and further enhanced the expression of chondrogenic genes. Moreover, this study established a rat model of ACLR and implanted the BMSCs-Exos/cartilage fragment complex into the femoral bone tunnel. Results demonstrated that the mean diameters of the femoral bone tunnels were significantly smaller in the BE-CF group than those in the CF group (p = 0.038) and control group (p = 0.007) at 8 weeks after surgery. Besides, more new bone formation was observed in the femoral tunnels in the BE-CF group, as demonstrated by a larger BV/TV ratio based on the reconstructed CT scans. Histological results also revealed the regeneration of tendon-bone structures, especially fibrocartilage. Thus, these findings provide a promising result that BMSCs-Exos/cartilage fragment complex can prevent the enlargement of bone tunnel and promote tendon-bone healing after ACLR, which may have resulted from the regulation of the BMP7/Smad5 signaling axis.

Multifunctional Drugs-Loaded Carbomol Hydrogel Promotes Diabetic Wound Healing via Antimicrobial and Immunoregulation.

Diabetic wound healing poses a significant clinical dilemma. Bacterial infection and immune dysregulation are the predominant reasons. However, conventional wound dressings with a single treatment approach often limit therapeutic efficacy and continue working with difficulty. These limitations cause high treatment failure for diabetic wounds. In this study, we developed a multiple drug-loaded carbomer hydrogel containing Que/Van/Rif (QVR-CBMG) for the simultaneous treatment of infection and immune dysregulation. Honeycomb-like QVR-CBMG hydrogel exhibits excellent abilities to eliminate bacterial infection and biofilms in vitro. Moreover, QVR-CBMG hydrogel possesses an immunomodulatory capacity via affecting the Sirt3/SOD2 signaling pathway to promote M2 macrophages. Furthermore, QVR-CBMG hydrogel effectively promotes wound healing in diabetic rats through several mechanisms. The multidrug-loaded wound dressing not only eliminates bacterial infection and facilitated angiogenesis but also promotes collagen deposition and remodulates the local immune microenvironment in the areas of wounds. In summary, this synthetic strategy to eliminate infection and regulate immune disorders has potential translational value for the prevention and management of diabetic wounds.

A Redox Homeostasis Modulatory Hydrogel with GLRX3+ Extracellular Vesicles Attenuates Disc Degeneration by Suppressing Nucleus Pulposus Cell Senescence.

Characterized by nucleus pulposus (NP) cell senescence and extracellular matrix (ECM) degradation, disc degeneration is a common pathology for various degenerative spinal disorders. To date, effective treatments for disc degeneration are absent. Here, we found that Glutaredoxin3 (GLRX3) is an important redox-regulating molecule associated with NP cell senescence and disc degeneration. Using a hypoxic preconditioning method, we developed GLRX3+ mesenchymal stem cell-derived extracellular vehicles (EVs-GLRX3), which enhanced the cellular antioxidant defense, thus preventing reactive oxygen species (ROS) accumulation and senescence cascade expansion in vitro. Further, a disc tissue-like biopolymer-based supramolecular hydrogel, which was injectable, degradable, and ROS-responsive, was proposed to deliver EVs-GLRX3 for treating disc degeneration. Using a rat model of disc degeneration, we demonstrated that the EVs-GLRX3-loaded hydrogel attenuated mitochondrial damage, alleviated the NP senescence state, and restored ECM deposition by modulating the redox homeostasis. Our findings suggested that modulation of redox homeostasis in the disc can rejuvenate NP cell senescence and thus attenuate disc degeneration.

Exosome-laden injectable self-healing hydrogel based on quaternized chitosan and oxidized starch attenuates disc degeneration by suppressing nucleus pulposus senescence.

Disc degeneration is the common pathology underlying various degenerative spinal disorders and currently there is no effective cure. Here, we found nucleus pulposus (NP) cell senescence was closely associated with the severity of disc degeneration, and exosomes (Exos) derived from mesenchymal stem cells (MSCs) ameliorated NP cell senescence and promoted extracellular matrix (ECM) deposition. As chitosan-based hydrogels have been widely used as vehicles to deliver Exos due to their prominent antibacterial capacity, biocompatibility, and biodegradability, we developed an Exos-laden hydrogel based on quaternized chitosan (QCS) and oxidized starch (OST) to treat disc degeneration. The synthesized QCS-OST hydrogel is injectable, self-healing, biocompatible, and demonstrated desirable pore size, injectable properties, and sustainable release of Exos. In a rat model of disc degeneration, the QCS-OST/Exos hydrogel was able to rejuvenate NP cell senescence, promote ECM remodeling, and partially restore the structures of NP and annulus fibrosis. Our findings suggested that the novel QCS-OST/Exos hydrogel is an effective therapeutic strategy for treating disc degeneration via alleviating NP cell senescence.

A Janus Au-Polymersome Heterostructure with Near-Field Enhancement Effect for Implant-Associated Infection Phototherapy.

Polymer-inorganic hybrid Janus nanoparticles (PI-JNPs) have attracted extensive attention due to their special structures and functions. However, achieving the synergistic enhancement of photochemical activity between polymer and inorganic moieties in PI-JNPs remains challenging. Herein, the construction of a novel Janus Au-porphyrin polymersome (J-AuPPS) heterostructure by a facile one-step photocatalytic synthesis is reported. The near-field enhancement (NFE) effect between porphyrin polymersome (PPS) and Au nanoparticles in J-AuPPS is achieved to enhance its near-infrared (NIR) light absorption and electric/thermal field intensity at their interface, which improves the energy transfer and energetic charge-carrier generation. Therefore, J-AuPPS shows a higher NIR-activated photothermal conversion efficiency (48.4%) and generates more singlet oxygen compared with non-Janus core-particle Au-PPS nanostructure (28.4%). As a result, J-AuPPS exhibits excellent dual-mode (photothermal/photodynamic) antibacterial and anti-biofilm performance, thereby significantly enhancing the in vivo therapeutic effect in an implant-associated-infection rat model. This work is believed to motivate the rational design of advanced hybrid JNPs with desirable NFE effect and further extend their biological applications.

Arbutin-modified microspheres prevent osteoarthritis progression by mobilizing local anti-inflammatory and antioxidant responses.

Osteoarthritis (OA) is a common degenerative joint disease worldwide and currently there is no effective strategy to stop its progression. It is known that oxidative stress and inflammation can promote the development of OA, and therapeutic strategies against these conditions may alleviate OA. Arbutin (ARB), a major ingredient of the Chinese medicinal herb cowberry leaf, exerts good antioxidant and anti-inflammatory activities yet has not been studied in OA. Here we developed ARB-loaded gelatine methacryloyl-Liposome (GM-Lipo@ARB) microspheres which showed long-term release of ARB and excellent cartilage-targeting effects. The ARB-loaded microspheres effectively reduced the inflammatory response in interleukin (IL)-1ß-treated arthritic chondrocytes. Moreover, the synthesized GM-Lipo@ARB microspheres regulated cartilage extracellular matrix (ECM) homeostasis through anti-inflammation effect via inhibiting NF-κB signaling and anti-oxidative stress effect via activating Nrf2 pathway. Intra-articular use of GM-Lipo@ARB can effectively reduce inflammation and oxidative stress in the articular cartilage and thus, attenuating OA progression in a mouse model. The study proposed a novel ARB-laden functional microsphere, GM-Lipo@ARB, and demonstrated that this compound may be used as an alternative therapeutics for treating OA.

Biomimetic Self-Assembling Metal-Organic Architectures with Non-Iridescent Structural Coloration for Synergetic Antibacterial and Osteogenic Activity of Implants.

Materials in nature feature versatile and programmable interactions to render macroscopic architectures with multiscale structural arrangements. By rationally combining metal-carboxylate and metal-organophosphate coordination interactions, Au25(MHA)18 (MHA, 6-mercaptohexanoic acid) nanocluster self-assembled structural color coating films and phytic acid (PA)-metal coordination complexes are sequentially constructed on the surface of titanium implants. The Lewis acid-base coordination principle applies for these metal-organic coordination networks. The isotropic arrangement of nanoclusters with a short-range order is investigated via grazing incidence wide-angle X-ray scattering. The integration of robust M-O (M = Ti, Zr, Hf) and labile Cu-O coordination bonds with high connectivity of Au25(MHA)18 nanoclusters enables these artificial photonic structures to achieve a combination of mechanical stability and bacteriostatic activity. Moreover, the colorless and transparent PA-metal complex layer allows the viewing of the structural color and surface wettability switching to hydrophilic and makes feasible the interfacial biomineralization of hydroxyapatite. Collectively, these modular metal-organic coordination-driven assemblies are predictive and rational material design strategies with tunable hierarchy and diversity. The complete metal-organic architectures will not only help improve the physicochemical properties of the bone-implant interface with synergistic antibacterial and osseointegration activities but also can boost surface engineering of medical metal implants.

A Combined Cyanine/Carbomer Gel Enhanced Photodynamic Antimicrobial Activity and Wound Healing.

As a non-invasive and non-specific therapeutic approach, photodynamic therapy (PDT) has been used to treat antibiotic-resistant bacteria with encouraging efficacy. Inspired by light, the photosensitizers can produce excessive reactive oxygen species (ROS) and, thus, effectively destroy or kill bacteria. Cyanine (Cy), a traditional photosensitizer for PDT, has the advantages of low cytotoxicity and high ROS yield. Yet, the water solubility and photostability for Cy are poor, which substantially limit its antibacterial efficiency and clinical translation. Herein, we combined Cy with carbomer gel (CBMG) to form a photodynamic Cy-CBMG hydrogel. In this system, Cy was evenly dispersed in CBMG, and CBMG significantly improved the water solubility and photostability of Cy via electrostatic interactions. The developed Cy-CBMG gel had less photodegradation under laser irradiation and thus can effectively elevate ROS accumulation in bacteria. The Cy-CBMG compound presented remarkable ROS-induced killing efficacy against methicillin-resistant Staphylococcus aureus (93.0%) and extended-spectrum ß-lactamase-producing Escherichia coli (88.7%) in vitro. Moreover, as a potential wound dressing material, the Cy-CBMG hydrogel exhibited excellent biocompatibility and effective antimicrobial ability to promote wound healing in vivo. Overall, this work proposed a practical strategy to synthesize a photosensitizer-excipient compound to enhance the photophysical property and antibacterial efficacy for PDT.

Lumbosacral Transitional Vertebra Contributed to Lumbar Spine Degeneration: An MR Study of Clinical Patients.

We aimed to comprehensively characterize degenerative findings associated with various types of lumbosacral transitional vertebra (LSTV) on magnetic resonance images. Three hundred and fifty patients with LSTV (52.3 ± 10.9 years), including 182 Castellvi type I, 107 type II, 43 type III, and 18 type IV, and 179 controls without LSTV (50.6 ± 13.1 years), were studied. Discs, endplates, and posterior vertebral structures were assessed and compared to those of controls for the most caudal three discs on MRIs. There were no differences in degenerative findings between patients with type I LSTV and controls. For types III and IV, the transitional discs had smaller sizes, lower Pfirrmann scores, and lower rates of disc bulging (2.3% and 5.6% vs. 39.1%), osteophytes (2.3% vs. 15.1%), disc herniation (2.3% and 5.6% vs. 31.8%), and Modic changes (2.3% and 5.6% vs. 16.8%) than controls. However, the cranial discs had more severe Pfirrmann scores, disc narrowing and spinal canal narrowing, and greater rates of disc herniation (41.9% and 50.0% vs. 25.7%), endplate defects (27.9% and 33.3% vs. 14.4%) and spondylolisthesis (18.6% vs. 7.3%) than controls. Type II LSTV was associated with degenerative findings in the cranial segments but to a lesser degree, as compared with type III/IV LSTV. Thus, Castellvi type III/IV LSTV predisposed the adjacent spinal components to degeneration and protected the transitional discs. Type II LSTV had significant effects in promoting transitional and adjacent disc degeneration. Type I LSTV was not related to spinal degeneration.

Effects of limonin treatment on the survival of random skin flaps in mice.

Random skin flap is commonly used in plastic and reconstructive surgery, however, distal part of skin flap often occurs ischemia and necrosis. Limonin, with bioactivities of anti-inflammation, anti-apoptosis and anti-oxidative stress, may be effective for skin flap survival. In our study, random flap model was performed in mice to explore the role of limonin in the survival of skin flap. On postoperative day 7, the necrosis of skin flaps was observed, while visualization of blood flow below the tissue surface was detected through Laser Doppler blood flow imaging (LDBFI). Then flap tissues were acquired to assess and levels of angiogenesis, apoptosis and oxidative stress. The results showed that limonin decreased necrosis and edema of skin flaps compared with the control group, with more blood flow in the flap under LDBFI detection. Limonin treatment also increased the mean vessels density, elevated the expression levels of angiogenic proteins (matrix metallopeptidase 9, vascular endothelial growth factor, Cadherin5) and antioxidant proteins [superoxide dismutase 1 (SOD1), endothelial nitric oxide synthase, heme oxygenase], and reduced the expression of apoptotic factors (BAX, CYC, Caspase3). In summary, limonin could effectively enhance the survival of random skin flap, the potential mechanism may attribute to the induction of angiogenesis, and inhibition of apoptosis and oxidative stress.

A poly (glycerol-sebacate-acrylate) nanosphere enhanced injectable hydrogel for wound treatment.

Wound repair remains a huge clinical challenge, which can cause bleeding, infection, and patient death. In our current research, a bioactive, injectable, multifunctional composite hydrogel doped with nanospheres was prepared with antibacterial and angiogenesis-promoting functions for the treatment of wounds. Amino groups in ε-polylysine (ε-EPL) undergo dynamic Schiff base reaction cross-linking with oxidized hyaluronic acid (OHA), and F127 exhibits unique temperature sensitivity to form an injectable thermosensitive hydrogel (FHE10), which can form a hydrogel to cover the wound at body temperature. Nanospheres (PNs) prepared using poly (glyceryl-sebacate-acrylate) (PGSA) were loaded into hydrogels (FHE10) for promoting wound repair. The prepared FHE10 exhibited rapid gelation, good injectable abilities, and showed resistance to the flourish of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In vitro investigations showed that FHE10 had good hemocompatibility and cytocompatibility. FHE10@PNs exhibited good proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) and human foreskin fibroblasts (HFF-1). Furthermore, FHE10@PNs significantly promoted reepithelialization and collagen deposition as well as micro-vascularization compared with the use of FHE10 or PNs alone, thereby accelerating the repair of wounds. In general, this study demonstrated that the multifunctional injectable composite hydrogel showed great potential in wound treatment.