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Cell condensation, linking the migration and chondrogenic differentiation of MSCs, plays a crucial role in cartilage development. Current cartilage repair strategies are inadequately concerned with this process, leading to a suboptimal quality of regenerated cartilage. Inspired by the "nest flocks" structure of Social Weavers, a degradable heterogeneous microgel assembly (F/S-MA) is developed, which can release SDF-1, to form a "micro-nest group" structure and bond with HAV peptides to promote cell recruitment, condensation and chondrogenic differentiation. First, slow-degrading microgels (S-microgels) grafted with HAV peptides and fast-degrading microgels (F-microgels) loaded with SDF-1 are fabricated by an amidation reaction and Schiff base reaction, respectively. They employ sulfhydryl-modified gelatin as assembling agents to form F/S-MA through a thiol-ene reaction, exhibiting injectability, tissue adhesion, and microporosity. F-microgels undergo rapid degradation, leading to the release of SDF-1 and the formation of a "micro-nest group" in F/S-MA. Consequently, F/S-MA exhibits cell recruitment ability, meanwhile facilitating BMSC condensation through the synergistic effects of the "micro-nest group" and HAV peptides. In vitro experiments prove that F/S-MA enhances the expression of cell-condensation-related markers, ultimately upregulating the secretion of cartilage matrix. Animal experiments show that F/S-MA optimizes the quality of regenerated cartilage by improving cell recruitment and condensation. F/S-MA enhances cell condensation through structural and component design, which will provide new insights for cartilage regeneration.

Myocardial infarction (MI) is a significant cardiovascular disease that restricts blood flow, resulting in massive cell death and leading to stiff and noncontractile fibrotic scar tissue formation. Recently, sustained oxygen release in the MI area has shown regeneration ability; however, improving its therapeutic efficiency for regenerative medicine remains challenging. Here, a combinatorial strategy for cardiac repair by developing cardioprotective and oxygenating hybrid hydrogels that locally sustain the release of stromal cell-derived factor-1 alpha (SDF) and oxygen for simultaneous activation of neovascularization at the infarct area is presented. A sustained release of oxygen and SDF from injectable, mechanically robust, and tissue-adhesive silk-based hybrid hydrogels is achieved. Enhanced endothelialization under normoxia and anoxia is observed. Furthermore, there is a marked improvement in vascularization that leads to an increment in cardiomyocyte survival by ≈30% and a reduction of the fibrotic scar formation in an MI animal rodent model. Improved left ventricular systolic and diastolic functions by ≈10% and 20%, respectively, with a ≈25% higher ejection fraction on day 7 are also observed. Therefore, local delivery of therapeutic oxygenating and cardioprotective hydrogels demonstrates beneficial effects on cardiac functional recovery for reparative therapy., (© 2024 Wiley‐VCH GmbH.)

Injectable hydrogels, offering adaptable drug delivery of growth factors (GFs), hold promise for treating bone defects. To optimize osteogenic efficacy, the release of GFs should mirror the natural bone healing. We developed an injectable thermo-responsive hydrogel/microgels platform for dual GF delivery for bone regeneration. Stromal cell-derived factor-1 alpha (SDF-1a) and the Methacrylate Gelatin (GelMA) microgels which encapsulated insulin-like growth factor-1 (IGF-1) loaded liposomes (Ls) were introduced into Poloxamer 407 (P407) hydrogel matrix. This system achieved the biomimetic release profile of SDF-1a and IGF-1, which covered the early stage from day 1 to 7 and the continuous stage from day 5 to 21, respectively. In vitro study confirmed the enhanced migration, osteogenic biomarker expression, and matrix mineralization of the bone marrow mesenchymal stem cells (BMSCs) co-cultivated with the dual GFs delivering hydrogel/microgels. Transcriptome sequencing revealed that the potential mechanism was associated with mitogen-activated protein kinase (MAPK) signaling activation and its downstream ribosomal protein S6 kinase 2 (RSK2) upregulation. In a critical-sized calvarial defect model in Sprague-Dawley (SD) rats, the injectable hydrogel/microgels system promoted significant bone regeneration. Collectively, our study suggested the current hydrogel/microgels system with the biomimetic release of SDF-1a and IGF-1 efficiently promoted bone regeneration, informing the future development of GF delivery systems intended for bone regeneration therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Refractory fracture presents an intractable challenge in trauma treatment. Selective polarization of macrophages as well as the recruitment of osteogenic precursor cells play key roles in osteogenic differentiation during fracture healing. Here we constructed regulatory T cell (Treg)-derived exosomes (Treg-Exo) for the treatment of fracture. The obtained exosomes displayed a spheroid shape with a hydrated particle size of approximately 130 nm. With further purification using CD39 and CD73 antibody-modified microfluidic chips, CD39 and CD73 specifically expressing exosomes were obtained. This kind of Treg-Exo utilized the ectonucleotidases of CD39 and CD73 to catalyze the high level of ATP in the fracture area into adenosine. The generated adenosine further promoted the selective polarization of macrophages. When interacting with mesenchymal stem cells (MSCs, osteogenic precursor cells), both Treg-Exo and Treg-Exo primed macrophages facilitated the proliferation and differentiation of MSCs. After administration in vivo, Treg-Exo effectively promoted fracture healing compared with conventional T cell-derived exosome. To further improve the delivery efficacy of exosomes and integrate multiple biological processes of fracture healing, an injectable hydrogel was fabricated to co-deliver Treg-Exo and stromal cell-derived factor 1 alpha (SDF-1α). With the dual effect of Treg-Exo for macrophage polarization and SDF-1α for MSC recruitment, the multifunctional hydrogel exerted a synergistic effect on fracture repair acceleration. This study provided a promising therapeutic candidate and synergistic strategy for the clinical treatment of fracture., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Endometrial injury is the main cause of intrauterine adhesions (IUA), and there is currently no effective prevention and treatment. Immune cells play an important role in damage repair by sensing the change in the microenvironment. Exogenous CXCL12 can promote tissue regeneration and repair by recruiting immune cells, but its effect and possible mechanism on endometrial regeneration and repair have not been reported. In the present study, we constructed an engineered a Lactobacillus crispatus strain by transforming a pMG36e plasmid carrying a CXCL12 gene into the bacterium, and developed two animal models, the intrauterine adhesion mice with or without diabetes to evaluate the positive effects of this strain on the prevention of IUA after accepting intrauterine surgery in normal and diabetic mice. The results showed that vaginal application of L. crispatus -pMG36e-mCXCL12 strains significantly diminished the levels of pro-inflammatory factors interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) in serum and uterine tissues of IUA mice, and resulted in the inhibition of the inflammatory (toll-like receptor 4/nuclear factor-κb, TLR4/NF-κB) and fibrotic (transforming growth factor-β1/smads, TGF-β1/Smads) signalling pathways in the uterine tissues. The high-throughput sequencing results further indicated that treatment with L. crispatus -pMG36e-mCXCL12 strains greatly increased the abundance of Lactobacillus spp. and reduced that of the pathogenic Klebsiella spp. in IUA mice. Furthermore, among intrauterine adhesion mice with diabetes, we obtained similar results to non-diabetic mice, that is, L.crispatus -pMG36e-mCXCL12 significantly improved fibrosis and inflammation in the uterine cavity of diabetic mice, and restored the vaginal microbiota balance in diabetic mice. Therefore, we speculated that vaginal administration of L. crispatus -pMG36e-mCXCL12 strains can effectively alleviate intrauterine adhesions by restoring the microbial balance and reducing inflammation and fibrosis caused by surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kong, Liu, Xiao, Wu, Hu, Deng and Chen.)

Non-viral gene delivery has become a popular approach in tissue engineering, as it permits the transient delivery of a therapeutic gene, in order to stimulate tissue repair. However, the efficacy of non-viral delivery vectors remains an issue. Our lab has created gene-activated scaffolds by incorporating various non-viral delivery vectors, including the glycosaminoglycan-binding enhanced transduction (GET) peptide into collagen-based scaffolds with proven osteogenic potential. A modification to the GET peptide (FLR) by substitution of arginine residues with histidine (FLH) has been designed to enhance plasmid DNA (pDNA) delivery. In this study, we complexed pDNA with combinations of FLR and FLH peptides, termed GET* nanoparticles. We sought to enhance our gene-activated scaffold platform by incorporating GET* nanoparticles into collagen-nanohydroxyapatite scaffolds with proven osteogenic capacity. GET* N/P 8 was shown to be the most effective formulation for delivery to MSCs in 2D. Furthermore, GET* N/P 8 nanoparticles incorporated into collagen-nanohydroxyapatite (coll-nHA) scaffolds at a 1:1 ratio of collagen:nanohydroxyapatite was shown to be the optimal gene-activated scaffold. pDNA encoding stromal-derived factor 1α (pSDF-1α), an angiogenic chemokine which plays a role in BMP mediated differentiation of MSCs, was then delivered to MSCs using our optimised gene-activated scaffold platform, with the aim of significantly increasing angiogenesis as an important precursor to bone repair. The GET* N/P 8 coll-nHA scaffolds successfully delivered pSDF-1α to MSCs, resulting in a significant, sustained increase in SDF-1α protein production and an enhanced angiogenic effect, a key precursor in the early stages of bone repair.

Subarachnoid hemorrhage (SAH) is a cerebrovascular disease associated with high morbidity and mortality. CXCR4 provides neuroprotective effects, which can alleviate brain injury and inflammation induced by stroke. Previous studies have suggested that CXCR4 reduces the pyroptosis of LPS-stimulated BV2 cells. The purpose of this study was to evaluate the antipyroptosis effects and mechanisms of CXCR4 after SAH. SAH animal model was induced via endovascular perforation. A total of 136 male Sprague-Dawley rats were used. Recombinant human cysteine-X-cysteine chemokine ligand 12 (rh-CXCL-12) was administered intranasally at 1 h after SAH induction. To investigate the underlying mechanism, the inhibitor of CXCR4, AMD3100, was administered intraperitoneally at 1 h before SAH. The neurobehavior tests were assessed, followed by performing Western blot and immunofluorescence staining. The Western blot results suggested that the expressions of endogenous CXCL-12, CXCR4, and NLRP1 were increased and peaked at 24 h following SAH. Immunofluorescence staining showed that CXCR4 was expressed on neurons, microglia, and astrocytes. Rh-CXCL-12 treatment improved the neurological deficits and reduced the number of FJC-positive cells, IL-18-positive neurons, and cleaved caspase-1(CC-1)-positive neurons after SAH. Meanwhile, rh-CXCL-12 treatment increased the levels of CXCL-12 and CXCR4, and reduced the levels of NLRP1, IL-18, IL-1 β , and CC-1. Moreover, the administration of AMD3100 abolished antipyroptosis effects of CXCL-12 and its regulation of CXCR4 post-SAH. The CXCR4/NLRP1 signaling pathway may be involved in CXCL-12-mediated neuronal pyroptosis after SAH. Early administration of CXCL-12 may be a preventive and therapeutic strategy against brain injury after SAH., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Ran Gu et al.)

Intervertebral disc (IVD) degeneration involves a complex cascade of events, including degradation of the native extracellular matrix, loss of water content, and decreased cell numbers. Cell recruitment strategies for the IVD have been increasingly explored, aiming to recruit either endogenous or transplanted cells. This study evaluates the IVD therapeutic potential of a chemoattractant delivery system (HAPSDF5) that combines a hyaluronan-based thermoreversible hydrogel (HAP) and the chemokine stromal cell derived factor-1 (SDF-1). HAPSDF5 was injected into the IVD and was combined with an intravenous injection of mesenchymal stem/stromal cells (MSCs) in a pre-clinical in vivo IVD lesion model. The local and systemic effects were evaluated two weeks after treatment. The hydrogel by itself (HAP) did not elicit any adverse effect, showing potential to be administrated by intradiscal injection. HAPSDF5 induced higher cell numbers, but no evidence of IVD regeneration was observed. MSCs systemic injection seemed to exert a role in IVD regeneration to some extent through a paracrine effect, but no synergies were observed when HAPSDF5 was combined with MSCs. Overall, this study shows that although the injection of chemoattractant hydrogels and MSC recruitment are feasible approaches for IVD, IVD regeneration using this strategy needs to be further explored before successful clinical translation.

Rapid and functional bone-tendon (B-T) healing remains a difficulty in clinical practice. Tissue engineering has emerged as a promising strategy to address this problem. However, the majority of tissue engineering scaffolds are loaded with stem cells to enhance the regenerability in B-T healing, which is complicated and inconvenient for clinical application. Accordingly, developing a cell-free scaffold with chemotactic function and chondrogenic inducibility may be an effective approach. In this study, a collagen affinity peptide derived from the A3 domain of von Willebrand factor (a hemostasis factor) was fused into the C-terminal of a stromal cell-derived factor-1α (SDF-1α) to synthesize a recombinant SDF-1α capable of binding collagen and chemotactic activity. The recombinant SDF-1α was then tethered on the collagen fibers of a book-shaped acellular fibrocartilage scaffold (BAFS), thus fabricating a novel scaffold (C-SDF-1α/BAFS) with chemotactic function and chondrogenic inducibility. In vitro tests determined that this scaffold was noncytotoxic and biomimetic, could attract stem cells migrating to the scaffold using sustainably released C-SDF-1α, and inducedthe interacting stem cells down the chondrogenic lineage. In vivo, the C-SDF-1α/BAFS significantly enhanced the B-T healing in a rabbit partial patellectomy model, as shown by the larger cartilaginous metaplasia region, better fibrocartilage regeneration, additional bone formation, and improved biomechanical properties. Therefore, the findings of the study demonstrate that the C-SDF-1α/BAFS could potentially be applied for B-T healing., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Objective: NLRP3 inflammasome may play a key role in OA pathogenesis. Stromal cell-derived factor-1 (SDF-1) is a homeostatic CXC chemokine. Since the role of SDF-1 in OA has not been explored, this study aimed to examine the effect of SDF-1 on NLRP3 inflammasome and pyroptosis in synoviocytes from OA joints., Materials and Methods: Human synovium was obtained from OA patients for isolation of primary synoviocytes and a murine model of collagenase-induced OA was established for testing intra-articular injections of SDF-1. Immunoblotting assays were used to examine the effects and underlying mechanism of action of SDF-1 on NLRP3 inflammasome and synoviocyte pyroptosis in synoviocytes. Inhibitors of AMPK and PI3K-mTOR were utilized to investigate the key signaling pathways involved in SDF-1-mediated OA inflammasome formation and pyroptosis., Results: Synoviocytes from OA joints exhibited significantly higher expression of NLRP3 inflammasome and biomarkers of synoviocyte pyroptosis relative to healthy individuals. This was confirmed in the collagenase-induced OA model, where OA synoviocytes had a significantly lower SDF-1 expression than healthy ones. SDF-1 treatment in synoviocytes of OA patients and collagenase-induced OA led to significant downregulation in the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers. Inhibition of the AMPK signaling pathway significantly suppressed the inhibitory effect of SDF-1 on NLRP3 inflammasome expression of OA synoviocytes. However, blocking the SDF-1-activated PI3K-mTOR signaling pathway could still suppress the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers., Conclusions: SDF-1 ameliorates NLRP3 inflammasome and pyroptosis in OA synoviocytes through activation of the AMPK signaling pathway. Therefore, SDF-1 may be a novel therapeutic target for OA.

Background: Stem cell therapy is among the novel approaches for the treatment of post-myocardial infarction cardiomyopathy. This study aims to compare the effect of stromal-derived factor 1 α (SDF1α), mesenchymal stem cells (MSCs) in combination with the lentiviral production of vascular endothelial growth factor (VEGF) on infarct area, vascularization and eventually cardiac function in a rat model of myocardial infarction (MI)., Methods: The influence of SDf1α on MSCs survival was investigated. MSCs were transduced via a lentiviral vector containing VEGF. After that, the effect of mesenchymal stem cell transfection of VEGF-A165 and SDf1α preconditioning on cardiac function and scar size was investigated in five groups of MI rat models. The MSC survival, cardiac function, scar size, angiogenesis, and lymphocyte count were assessed 72 hours and 6 weeks after cell transplantation., Results: SDF1α decreased the lactate dehydrogenase release in MSCs significantly. Also, the number of viable cells in the SDF1α-pretreated group was meaningfully more than the control. The left ventricular systolic function significantly enhanced in groups with p240 MSC, SDF1α MSC, and VEGF-A165 MSC in comparison to the control group., Conclusions: These findings suggest that SDF1α pretreatment and overexpressing VEGF in MSCs could augment the MSCs' survival in the infarcted myocardium, reduce the scar size, and improve the cardiac systolic function., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Stem cell-based approaches have become a promising therapeutic strategy for treating ischemic diseases. The aim of this study was to develop injectable hydrogel systems for the local release of stromal cell-derived factor-1α (SDF-1α) to recruit adipose stem cells (ASCs) that express CXCR4 to achieve stem cell therapy and therapeutic angiogenesis. Thermoresponsive and injectable chitosan (CS)/β-glycerophosphate disodium salt pentahydrate (βGP) hydrogels with different concentrations of hyaluronic acid (HA) were designed and fabricated to achieve local and sustained release of SDF-1α for ASC recruitment. Herein, the material structures, physical properties, gelation temperature, and gelation time of hydrogels with different compositions were determined. The incorporation of 0.9% HA in CS-based hydrogels not only enhanced the gelation time but also increased the strength of the hydrogels. In addition, the results revealed that the thermoresponsive and injectable CS/βGP/HA hydrogels showed good biocompatibility. In addition, the in vitro release profiles showed that the hydrogels achieved sustained release of SDF-1α over 7 days and enhanced ASC migration. The results revealed that the hydrogels with HA enhanced the sustained release effect compared with the hydrogel without HA, indicating that the HA content regulated the physical and release properties of the injectable hydrogels. Therefore, thermoresponsive and injectable CS/βGP/HA hydrogels may provide an alternative for treating ischemic diseases via SDF-1/CXCR4 axis for ASC recruitment and retention.

The present study was conducted to assess the effects of AMD3100 and stromal cell-derived factor 1 (SDF-1) on cellular functions and endothelial regeneration of endothelial progenitor cells (EPCs). The cell proliferation and adhesion capacity of EPCs were evaluated in vitro following treatment with AMD3100 and SDF‑1 using a Cell Counting Kit‑8 assay. Furthermore, the expression levels of C‑X‑C motif chemokine receptor 4 (CXCR4) and C‑X‑C motif chemokine receptor 7 (CXCR7) were detected before and after treatment with AMD3100 and SDF‑1 to elucidate their possible role in regulating the cellular function of EPCs. A rat carotid artery injury model was established to assess the influences of AMD3100 and SDF‑1 on endothelial regeneration. AMD3100 reduced the proliferation and adhesion capacity of EPCs to fibronectin (FN), whereas it increased the adhesion capacity of EPCs to human umbilical vein endothelial cells (HUVECs). However, SDF‑1 stimulated the proliferation and cell adhesion capacity of EPCs to HUVECs and FN. Additionally, the expression levels of CXCR7 but not CXCR4 were upregulated following AMD3100 treatment, whereas the expression levels of both CXCR4 and CXCR7 were upregulated after SDF‑1 treatment. In vivo results demonstrated that AMD3100 increased the number of EPCs in the peripheral blood and facilitated endothelial repair at 7 days after treatment. However, local administration of SDF‑1 alone did not enhance reendothelialization 7 and 14 days after treatment. Importantly, the combination of AMD3100 with SDF‑1 exhibited superior therapeutic effects compared with AMD3100 treatment alone, accelerated reendothelialization 7 days after treatment, and attenuated neointimal hyperplasia at day 7 and 14 by recruiting more EPCs to the injury site. In conclusion, AMD3100 could positively regulate the adhesion capacity of EPCs to HUVECs via elevation of the expression levels of CXCR7 but not CXCR4, whereas SDF‑1 could stimulate the proliferation and adhesion capacity of EPCs to FN and HUVECs by elevating the expression levels of CXCR4 and CXCR7. AMD3100 combined with SDF‑1 outperformed AMD3100 alone, promoted early reendothelialization and inhibited neointimal hyperplasia, indicating that early reendothelialization attenuated neointimal hypoplasia following endothelial injury.

The complex process of wound healing can be delayed in circumstances when the natural niche is extremely altered. Adipose-derived stem cells (ADSC) seem to be a promising therapy for these type of wounds. We aim to describe the studies that used ADSC for wound healing after a full-thickness skin defect, the ADSC mechanisms of action, and the outcomes of the different ADSC therapies applied to date. We performed a review by querying PubMed database for studies that evaluated the use of ADSC for wound healing. The Mesh terms, adipose stem cells AND (skin injury OR wound healing) and synonyms were used for the search. Our search recorded 312 articles. A total of 30 articles met the inclusion criteria. All were experimental in nature. ADSC was applied directly (5 [16.7%]), in sheets (2 [6.7%]), scaffolds (14 [46.7%]), skin grafts (3 [10%]), skin flaps (1 [3.3%]), as microvesicles or exosomes (4 [13.3%]), with adhesives for wound closure (1 [3.3%]), and in a concentrated conditioned hypoxia-preconditioned medium (1 [3.3%]). Most of the studies reported a benefit of ADSC and improvement of wound healing with all types of ADSC therapy. ADSC applied along with extracellular matrix, stromal cell-derived factor (SDF-1) or keratinocytes, or ADSC seeded in scaffolds showed better outcomes in wound healing than ADSC alone. ADSC have shown to promote angiogenesis, fibroblast migration, and up-regulation of macrophages chemotaxis to enhance the wound healing process. Further studies should be conducted to assure the efficacy and safety of the different ADSC therapies.

We developed a stromal cell-derived factor-1 alpha (SDF-1α)-aligned silk fibroin (SF)/three-dimensional porous bladder acellular matrix graft (3D-BAMG) composite scaffold for long-section ventral urethral regeneration and repair in vivo. SDF-1α-aligned SF microfiber/3D-BAMG, aligned SF microfiber/3D-BAMG, and nonaligned SF microfiber/3D-BAMG scaffolds were prepared using electrostatic spinning and wet processing. Adipose-derived stem cell (ADSC) and bone marrow stromal cell (BMSC) migration was assessed in the SDF-1α-loaded scaffolds. Sustained SDF-1α release in vitro and vivo was analyzed using enzyme-linked immunosorbent assay (ELISA) and western blotting, respectively. The scaffolds were used to repair a 1.5 × 1 cm 2 ventral urethral defect in male rabbits in vivo. General observation and retrograde urinary tract contrast assessment were used to examine urethral lumen patency and continuity at 1 and 3 months post-surgery. Postoperative rehabilitation was evaluated using histological detection. The composite scaffolds sustained SDF-1α release for over 16 days in vitro. SDF-1α-aligned SF nanofiber promoted regeneration of urethral mucosa, submucosal smooth muscles, and microvasculature, increased cellular proliferation, and reduced collagen deposition. SDF-1α expression was increased in reconstructed urethra at 3 months post-surgery in SDF-1α-aligned SF group. SDF-1α-aligned SF microfiber/3D-BAMG scaffolds may be used to repair and reconstruct long urethral defects because they accelerate urethral regeneration., (© 2020 Wiley Periodicals, Inc.)

We compared therapeutic properties of natural and engineered chemokine (C-X-C motif) receptor 4 (CXCR4) agonists in a rat acute respiratory distress syndrome (ARDS) model utilizing the PaO 2 /FiO 2 -ratio as a clinically relevant primary outcome criterion. Ventilated rats underwent unilateral lung ischemia from t = 0-70 min plus hemorrhage to a mean arterial blood pressure (MAP) of 30 mmHg from t = 40-70 min, followed by reperfusion/fluid resuscitation until t = 300 min. Natural CXCR4 agonists (CXCL12, ubiquitin) and engineered CXCL12 variants (CXCL12 1 , CXCL2 2 , CXCL12K27A/R41A/R47A, CXCL12 (3-68)) were administered within 5 min of fluid resuscitation. Animals treated with vehicle or CXCL12 (3-68) reached criteria for mild and moderate ARDS between t = 90-120 min and t = 120-180 min, respectively, and remained in moderate ARDS until t = 300 min. Ubiquitin, CXCL12, CXCL12 1 and CXCL12 2 prevented ARDS development. Potencies of CXCL12/CXCL12 1 /CXCL12 2 were higher than the potency of ubiquitin. CXCL12K27A/R41A/R47A was inefficacious. CXCL12 1  > CXCL12 stabilized MAP and reduced fluid requirements. CXCR4 agonists at doses that preserved lung function reduced histological injury of the post-ischemic lung and reduced mortality from 55 to 9%. Our findings suggest that CXCR4 protein agonists prevent development of ARDS and reduce mortality in a rat model, and that development of new engineered protein therapeutics with improved pharmacological properties for ARDS is possible.

In this contribution, an injectable hydrogel was developed with chitosan, gelatin, β-glycerphosphate and Arg-Gly-Asp (RGD) peptide: this hydrogel is liquid in room temperature and rapidly gels at 37 °C; RGD peptide promises better growth microenvironment for various cells, especially endothelial cells (EC), smooth muscle cells (SMC) and mesenchymal stem cells (MSC). Both stromal cell-derived factor-1 (SDF-1) nanoparticle and vascular endothelial growth factor (VEGF) nanoparticles were loaded in the injectable hydrogel to simulate the natural nanoparticles in the extracellular matrix (ECM) to promote angiogenesis. In vitro EC/SMC and MSC/SMC co-culture experiment indicated that the nanocomposite hydrogel accelerated constructing embryonic form of blood vessels, and chick embryo chorioallantoic membrane model demonstrated its ability of improving cells migration and blood vessel regeneration. We injected this nanocomposite hydrogel into rat myocardial infarction (MI) model and the results indicated that the rats heart function recovered better compared control group. We hope this injectable nanocomposite hydrogel may possess wider application in tissue engineering.

Background: The development of drug delivery systems has enabled the release of multiple bioactive molecules. The efficacy of nerve conduits coated with dual controlled release of stromal cell-derived factor-1 (SDF-1) and basic fibroblast growth factor (bFGF) for peripheral nerve regeneration was investigated., Materials and Methods: Sixty-two C57BL6 mice were used for peripheral nerve regeneration with a nerve conduit (inner diameter, 1 mm, and length, 7 mm) and an autograft. The mice were randomized into five groups based on the different repairs of nerve defects. In the group of repair with conduits alone (n = 9), a 5-mm sciatic nerve defect was repaired by the nerve conduit. In the group of repair with conduits coated with bFGF (n = 10), SDF-1 (n = 10), and SDF-1/bFGF (n = 10), it was repaired by the nerve conduit with bFGF gelatin, SDF-1 gelatin, and SDF-1/bFGF gelatin, respectively. In the group of repair with autografts (n = 10), it was repaired by the resected nerve itself. The functional recovery, nerve regeneration, angiogenesis, and TGF-β1 gene expression were assessed., Results: In the conduits coated with SDF-1/bFGF group, the mean sciatic functional index value (-88.68 ± 10.64, p = .034) and the axon number (218.8 ± 111.1, p = .049) were significantly higher than the conduit alone group, followed by the autograft group; in addition, numerous CD34-positive cells and micro vessels were observed. TGF-β1 gene expression relative values in the conduits with SDF-1/bFGF group at 3 days (7.99 ± 5.14, p = .049) significantly increased more than the conduits alone group., Conclusion: Nerve conduits coated with dual controlled release of SDF-1 and bFGF promoted peripheral nerve regeneration., (© 2019 Wiley Periodicals, Inc.)

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that leads to disability in middle-aged individuals. High rates of apoptosis and inappropriate homing are limitations for the application of stem cells in cell therapy. Preconditioning of bone marrow mesenchymal stem cells (BMSCs) with stromal cell-derived factor 1α (SDF-1α), also called C-X-C motif chemokine 12 (CXCL12), is an approach for improving the functional features of the cells. The aim of this study was to investigate the therapeutic efficacy of intranasal delivery of SDF-1α preconditioned BMSCs in the cuprizone-induced chronically demyelinated mice model. BMSCs were isolated, cultured, and preconditioned with SDF-1α. Then, intranasal delivery of the preconditioned cells was performed in the C57BL/6 mice receiving cuprizone for 12 weeks. Animals were killed at 30 days after cell delivery. SDF-1α preconditioning increased C-X-C chemokine receptor type 4 (CXCR4) expression on the surface of BMSCs, improved survival of the cells, and decreased their apoptosis in vitro. SDF-1α preconditioning also improved CXCL12 level within the brain, and enhanced spatial learning and memory (assessed by Morris water maze [MWM]), and myelination (assessed by Luxol fast blue [LFB] and transmission electron microscopy [TEM]). In addition, preconditioning of BMSCs with SDF-1α reduced the protein expressions of glial fibrillary acidic protein and ionized calcium-binding adapter molecule (Iba-1) and increased the expressions of oligodendrocyte lineage transcription factor-2 (Olig-2) and adenomatous polyposis coli (APC), evaluated by immunofluorescence. The results showed the efficacy of intranasal delivery of SDF-1α-preconditioned BMSCs for improving remyelination in the cuprizone model of MS., (© 2019 International Federation for Cell Biology.)

Herein we report a facile approach for chitosan-heparin hydrogels with controlled release manner and their applications for intrauterine adhesion. The sol precursor was converted to gel at physiological temperature in 15 min. FTIR, SEM and swelling test were performed to characterize their compositions, morphologies and stability. In vitro releasing profiles was investigated in PBS solutions. Intrauterine injured rat model was established and treated with different methods. The results of H&E staining, Masson trichrome staining, western blots assay, immunohistochemical staining and immunofluorescence staining revealed that endogenous c-kit positive stem cells (HSCs) were recruited to the injury site and promoted the wound recovery. After 7 days' treatment, uterus treated with SDF-1α releasing hydrogel showed no difference with control group on endometrial thickness, glands number and fibrosis level. This work provides a possible method for intrauterine adhesion healing., (Copyright © 2019 Elsevier B.V. All rights reserved.)

CXCL12 is a chemokine known to regulate migration, proliferation, and differentiation of neural stem cells (NSCs) and to play a neuroprotective role in ischemic stroke. Chitosan-dextran sulfate nanocomplexes (Ch/DS NC) are known nanoparticulated systems used to efficiently deliver heparin-binding factors. Here we evaluate Ch/DS NC as carriers for CXCL12 in a mouse model of stroke. Free CXCL12 reduced the size of the ischemic brain lesion. However, when Ch/DS NC were administrated, the stroke volume increased. Neurotoxic screening revealed that Ch/DS NC reduced neuronal viability, decreased the extension of neurites and impaired NSC migration in vitro. To the best of our knowledge, neurotoxicity of Ch/DS NC has not been reported and further screenings will be needed in order to evaluate the biological safety of these nanocomposites. Our results add new data on nanoparticle neurotoxicity and may help us to better understand the complex interactions of the nanostructures with biological components., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To investigate the effect of CXCL12 on regeneration of radial glia like cells after traumatic brain injury (TBI). We randomly divided 48 rats into 4 groups: (1) the sham group, rats were performed craniotomy only, (2) the control group, saline were injected into the ipsilateral cortex after TBI, (3) the CXCL12 group, CXCL12 were injected, and (4) the CXCL12 + AMD3100 group, a mixture of CXCL12 and AMD3100 were injected. Seven days after TBI, the brain tissues were subjected to immunofluorescence double-labeled staining of BrdU/Nestin, BLBP/Nestin, BLBP/Vimentin, BLBP/SOX2, BLBP/CXCR4, BLBP/DCX. Western Blot assay was used to measure the levels of Nestin, BLBP, and Vimentin. Compared with the control group, CXCL12 treatment significantly increased the number of cells stained with BrdU/Nestin, BLBP/Nestin, and BLBP/Vimentin around the injured cortex and corpus callosum areas. CXCL12 + AMD3100 treatment significantly decreased the number of these cells compared with the CXCL12 treatment and control group. The protein levels of Nestin, BLBP, and Vimentin had the same change trends as those of the immunofluorescence staining. The BLBP/Vimentin positive cells presented with the astrocyte pattern around the injured cortex area but with the RGCs pattern around the injured corpus callosum area. The BLBP positive cells also expressed CXCR4 and SOX2. Altogether, CXCL12 promotes the proliferation of neural precursor cells after TBI by combing to its receptor, CXCR4. The proliferating neural precursor cells presents radial glial cell like cells. The RGCs-like cells can differentiate into immature neurons and promote the migration of immature neurons., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Chemokine receptor CXCR4 has been found to be associated with spinal neuron and glial cell activation during bone cancer pain. However, the underlying mechanism remains unknown. Furthermore, the RhoA/ROCK2 pathway serves as a downstream pathway activated by CXCR4 during bone cancer pain. We first validated the increase in the expressions of CXCR4, p-RhoA, and p-ROCK2 in the spinal dorsal horn of a well-characterized tumor cell implantation-induced cancer pain rat model and how these expressions contributed to the pain behavior in tumor cell implantation rats. We hypothesized that spinal blockade of the CXCR4-RhoA/ROCK2 pathway is a potential analgesic therapy for cancer pain management., Methods: Adult female Sprague-Dawley rats (body weight of 180-220 g) and six- to seven-week old female Sprague-Dawley rats (body weight of 80-90 g) were taken. Ascitic cancer cells were extracted from the rats (body weight of 80-90 g) with intraperitoneally implanted Walker 256 mammary gland carcinoma cells. Walker 256 rat mammary gland carcinoma cells were then injected (tumor cell implantation) into the intramedullary space of the tibia to establish a rat model of bone cancer pain., Results: We found increased expressions of CXCR4, p-RhoA, and p-ROCK2 in the neurons in the spinal cord. p-RhoA and p-ROCK2 were co-expressed in the neurons and promoted by overexpressed CXCR4. Intrathecal delivery of CXCR4 inhibitor Plerixafor (AMD3100) or ROCK2 inhibitor Fasudil abrogated tumor cell implantation-induced pain hypersensitivity and tumor cell implantation-induced increase in p-RhoA and p-ROCK2 expressions. Intrathecal injection of stromal-derived factor-1, the principal ligand for CXCR4, accelerated p-RhoA expression in naive rats, which was prevented by postadministration of CXCR4 inhibitor Plerixafor (AMD3100) or ROCK2 inhibitor Fasudil., Conclusions: Collectively, the spinal RhoA/ROCK2 pathway could be a critical downstream target for CXCR4-mediated neuronal sensitization and pain hypersensitivity in bone cancer pain, and it may serve as a potent therapeutic target for pain treatment.

Because the collagen membrane lacks osteoinductivity, it must be modified with bioactive components to trigger rapid bone regeneration. In this study, we aimed to evaluate the bone regeneration effects of a collagen membrane chemically conjugated with stromal cell-derived factor-1 alpha (SDF-1α) in rat models. To this end, different collagen membranes from four groups including a control group with a Bio-Oss bone substitute + collagen membrane; physical adsorption group with Bio-Oss + SDF-1α physically adsorbed on the collagen membrane; chemical cross-linking group with Bio-Oss + SDF-1α chemically cross-linked to the collagen membrane; and cell-seeding group with Bio-Oss + bone marrow mesenchymal stem cells (BMSCs) seeded onto the collagen membrane were placed in critical-sized defect models using a guided bone regeneration technique. At 4 and 8 weeks, the specimens were analyzed by scanning electron microscopy, energy-dispersive x-ray spectroscopy, micro-computed tomography, and histomorphology analyzes. Furthermore, ectopic osteogenesis was examined by histological analysis with Von Kossa staining, with the samples counterstained by hematoxylin and eosin and immunohistochemical staining. The results showed that in the chemical cross-linking group and cell-seeding group, the bone volume fraction, bone surface area fraction, and trabecular number were significantly increased and showed more new bone formation compared to the control and physical adsorption groups. Von Kossa-stained samples counterstained with hematoxylin and eosin and subjected to immunohistochemical staining of 4-week implanted membranes revealed that the chemical cross-linking group had the largest number of microvessels. The collagen membrane chemically conjugated with SDF-1α to significantly promote new bone and microvessel formation compared to SDF-1α physical adsorption and showed similar effects on new bone formation as a BMSC seeding method. This study provided a cell-free approach for shortening the bone healing time and improving the success rate of guided bone regeneration.

The development of a novel alloplastic graft with both osteoinductive and osteoconductive properties is still necessary. In this study, we tried to synthesize a biomimetic hydroxyapatite microspheres (gelatin/nano-hydroxyapatite microsphere embedded with stromal cell-derived factor-1: GHM-S) from nanocrystalline hydroxyapatites and to investigate their therapeutic potential and effects on bone regeneration. In this study, hydroxyapatite was synthesized by co-precipitation of calcium hydroxide and orthophosphoric acid to gelatin solution. The microbial transglutaminase was used as the agent to crosslink the microspheres. The morphology, characterization, and thermal gravimetric analysis of microspheres were performed. SDF-1 release profile and in vitro biocompatibility and relative osteogenic gene expression were analyzed, followed by in vivo micro-computed tomography study and histological analysis. The synthesized hydroxyapatite was found to be similar to hydroxyapatite of natural bone tissue. The stromal cell-derived factor-1 was embedded into gelatin/hydroxyapatite microsphere to form the biomimetic hydroxyapatite microsphere. The stromal cell-derived factor-1 protein could be released in a controlled manner from the biomimetic hydroxyapatite microsphere and form a concentration gradient in the culture environment to attract the migration of stem cells. Gene expression and protein expression indicated that stem cells could differentiate or develop into pre-osteoblasts. The effect of bone formation by the biomimetic hydroxyapatite microsphere was assessed by an in vivo rats' alveolar bone defects model and confirmed by micro-CT imaging and histological examination. Our findings demonstrated that the biomimetic hydroxyapatite microsphere can enhance the alveolar bone regeneration. This design has potential be applied to other bone defects.

Background: Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification and disordered angiogenesis. Stromal derived factor-1 (SDF-1) is a chemokine which modulates cell migration, proliferation, and angiogenesis. Here we tested the hypothesis that intra-tracheal (IT) administration of a naked plasmid DNA expressing SDF-1 would attenuate neonatal hyperoxia-induced lung injury in an experimental model of BPD, by promoting angiogenesis., Design/methods: Newborn Sprague-Dawley rat pups (n = 18-20/group) exposed to room air (RA) or hyperoxia (85% O2) from postnatal day (P) 1 to 14 were randomly assigned to receive IT a naked plasmid expressing SDF-1, JVS-100 (Juventas Therapeutics, Cleveland, Ohio) or placebo (PL) on P3. Lung alveolarization, angiogenesis, inflammation, vascular remodeling and pulmonary hypertension (PH) were assessed on P14. PH was determined by measuring right ventricular systolic pressure (RVSP) and the weight ratio of the right to left ventricle + septum (RV/LV + S). Capillary tube formation in SDF-1 treated hyperoxia-exposed human pulmonary microvascular endothelial cells (HPMEC) was determined by matrigel assay. Data is expressed as mean ± SD and analyzed by two-way ANOVA., Results: Exposure of neonatal pups to 14 days of hyperoxia decreased lung SDF-1 gene expression. Moreover, whilst hyperoxia exposure inhibited capillary tube formation in HPMEC, SDF-1 treatment increased tube length and branching in HPMEC. PL-treated hyperoxia-exposed pups had decreased alveolarization and lung vascular density. This was accompanied by an increase in RVSP, RV/LV + S, pulmonary vascular remodeling and inflammation. In contrast, IT JVS-100 improved lung structure, reduced inflammation, PH and vascular remodeling., Conclusions: Intratracheal administration of a naked plasmid expressing SDF-1 improves alveolar and vascular structure in an experimental model of BPD. These findings suggest that therapies which modulate lung SDF-1 expression may have beneficial effects in preterm infants with BPD.

Severe infection and mechanical injury of the uterus may lead to infertility and miscarriage. Currently, there is a lack of effective treatment modality for functional repair of uterine injury. To address this clinical challenge, this study aimed to develop a chemotactic composite scaffold by incorporating recombinant human stromal cell-derived factor-1α (rhSDF-1α) into a silk fibroin-bacterial cellulose (SF-BC) membrane carrier. A rat model of uterine injury was utilized for this study, which was composed of three groups as follows: blank control, implantation with SF-BC only, or SF-BC loaded with rhSDF-1α. The tissue regeneration efficacy of the three groups was analyzed and compared. The results showed that SF-BC loaded with rhSDF-1α significantly enhanced endometrial regeneration and arteriogenesis of the injured rat uterus, which led to improved pregnancy outcomes, thus indicating much promise for functional uterine repair and regeneration. Impact Statement In this study, we demonstrated that the silk fibroin-bacterial cellulose (SF-BC) membrane possessed good physical, chemical, and biocompatibility properties in vitro . The in vivo study showed that the incorporation of recombinant human stromal cell-derived factor-1α (rhSDF-1α) within the SF-BC membrane promoted regeneration of full-thickness uterine injury and also improved the pregnancy outcome of the damaged uterus. The results thus suggest that SF-BC loaded with rhSDF-1α has good potential in future clinical applications for the repair of uterine injury.

Background: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with a poor prognosis. Fibroblast proliferation amplifies extracellular matrix deposition and increases angiogenesis. Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic factors. VEGF interacts with VEGF receptors (VEGFR1 and VEGFR2). A previous study showed that VEGFR1 tyrosine kinase (TK) signaling induced blood flow recovery mediated by bone marrow (BM)-derived stem cells. We hypothesized that VEGFR1-TK signaling might be related to pulmonary fibrosis., Material and Methods: Six-week-old male C57Bl/6 wild-type (WT) mice and VEGFR1 TK knockout mice (TKKO mice) were treated with a single intratracheal injection of bleomycin (BLM; 0.1 μg in 50 μl saline) or vehicle (saline; 50 μl). Lung fibrosis was evaluated by histology, real-time PCR and ELISA for pro-fibrotic factors, and assessment of lung mechanics., Results: The fibrotic area in the lung and the lung elastance were significantly reduced in TKKO mice (P < 0.01). The expression of the fibrosis-related factors type I collagen, S100A4, and transforming growth factor (TGF)-β was also significantly reduced in TKKO mice on day 21 after BLM injection. TKKO mice also had significantly lower levels of stromal cell-derived factor (SDF)-1 in the lungs and plasma on days 14 and 21 after BLM treatment (P < 0.05). Moreover, the expression of C-X-C chemokine receptor type 7 (CXCR7) and CXCR4, the receptors for SDF-1, was also suppressed in TKKO mice. Immunohistochemical analysis showed that treatment with a CXCR4 antibody decreased the accumulation of VEGFR1 + cells in the lung in WT mice but not in TKKO mice., Conclusion: These results suggest that VEGFR1 TK signaling promotes BLM-induced pulmonary fibrosis by activating the SDF-1/CXCR4 axis in infiltrating VEGFR1 + cells., (Copyright © 2019. Published by Elsevier Masson SAS.)

Development of distant metastasis relies on interactions between cancer and stromal cells. CXCL12, also known as stromal-derived factor 1α (SDF-1α), is a major chemokine constitutively secreted in bone marrow, lymph nodes, liver and lung, playing a critical role in the migration and seeding of neoplastic cells. CXCL12 activates the CXCR4 receptor that is overexpressed in several human cancer cells. Recent evidence reveals that tumors induce pre-metastatic niches in target organ producing tumor-derived factors. Pre-metastatic niches represent a tumor growth-favoring microenvironment in absence of cancer cells. A commercially available dermal filler, hyaluronic acid (HA) -based gel, loaded with CXCL12 (CLG) reproduced a "fake" pre-metastatic niche. In vitro, B16-hCXCR4-GFP, human cxcr4 expressing murine melanoma cells efficiently migrated toward CLG. In vivo, CLGs and empty gels (EGs) were subcutaneously injected into C57BL/6 mice and 5 days later B16-hCXCR4-GFP cells were intravenously inoculated. CLGs were able to recruit a significantly higher number of B16-hCXCR4-GFP cells as compared to EGs, with reduced lung metastasis in mice carrying CLG. CLG were infiltrated by higher number of CD45-positive leukocytes, mainly neutrophils CD11b+Ly6G+ cells, myeloid CD11b+Ly6G- and macrophages F4/80. CLG recovered cells recapitulated the features of B16-hCXCR4-GFP (epithelial, melanin rich, MELAN A/ S100/ c-Kit/CXCR4 pos; α-SMA neg). Thus a HA-based dermal filler loaded with CXCL12 can attract and trap CXCR4+tumor cells. The CLG trapped cells can be recovered and biologically characterized. As a corollary, a reduction in CXCR4 dependent lung metastasis was detected.

Background: This study aimed to investigate the effects of stromal cell-derived factor-1 (SDF-1) on biphasic ceramic-like biologic bone (BCBB) in vivo on the repair of large segment bone defect in rabbits., Methods: A large-segment radius defect model of the rabbits was constructed. In the experimental group, BCBB with SDF-1 sustained-release system were implanted into the bone defect site. Other three groups including normal control, autologous bone graft, and BCBB implantation without SDF-1 were set. After surgery, general observation, X-ray radiography and scoring, and tissue section staining were performed at 2, 4, 8, 12, and 24 weeks post-implantation., Results: By general observation, X-ray radiography and grading and tissue section staining observation, we found that the BCBB carrying SDF-1 was better than those in the group of BCBB without SDF-1 (P < 0.05). BCBB scaffold had certain bone conduction capacity, and the BCBB scaffold carrying SDF-1 had improved bone conduction ability and possessed bone induction ability. In the case of carrying SDF-1, it can be used to repair large bone defects in a shorter time than simply using BCBB, which is equivalent to the effect of autologous bone., Conclusion: BCBB scaffold carrying SDF-1 can promote the repair effect on a large bone defect, which is equivalent to the effect of autologous bone.

Purpose of Review: Update on recent regenerative medicine approaches to the treatment of stress urinary incontinence (SUI) caused by intrinsic sphincter deficiency (ISD)., Recent Findings: In the treatment of female SUI/ISD, results using different types of cellular therapy have been disappointing, and new approaches are desirable. To advance our regenerative medicine approaches to SUI/ISD, it is critical to utilize animal models that best parallel the pathophysiology of this disease in women. Many current animal models mimic acute SUI/ISD. However, SUI/ISD in women is usually a chronic condition resulting from previous muscle and nerve sphincter damage during parturition or muscle loss during aging. Similar to women, a nonhuman primate (NHP) model of chronic SUI/ISD has demonstrated only modest response to cell therapy. However, treatment with stromal cell-derived factor 1 (SDF1), also known as C-X-C motif chemokine 12 (CXCL12) restored continence in this model., Summary: As a potential therapeutic approach, the use of a well characterized chemokine, such as CXCL12, may by-pass the lengthy and expensive process of cell isolation, expansion, and injection. Recent findings in this new NHP model of chronic SUI/ISD may open up the field for noncell-based treatments.

The combination of photothermal therapy and targeted chemotherapy can produce much greater cytotoxicity than chemotherapy. Herein, we developed multifunctional targeted polymeric nanoparticles (NPs) loaded with indocyanine green (ICG) and doxorubicin (DOX) for the targeted photoacoustic imaging and photothermal ablation of oral cancer cells. The chemokine SDF-1, a specific antibody, was conjugated to NPs by the carbodiimide method. The NPs were automatically targeted to tumour tissue in vitro and in vivo through CXCR4-SDF-1 interactions. The results of in vivo and in vitro photoacoustic imaging and photothermal therapy experiments showed that the multifunctional NPs had excellent photoacoustic imaging characteristics and photothermal therapy capabilities. The photothermal material heated rapidly after laser irradiation, and the resulting heat increased cell metabolism and membrane permeability, which increased cellular NP uptake. The encapsulated drug (DOX) was released immediately after the liquid core was transformed into a gas via laser effects, which killed tumour cells while producing strong photoacoustic signals in vitro and in vivo. Thus, we concluded that the chemokine SDF-1 can be applied for the targeted chemotherapy of metastatic lymph nodes of oral squamous cell carcinoma (OSCC) and is more effective for treating oral cancer when combined with photothermal therapy than when used alone., (Copyright © 2018. Published by Elsevier B.V.)

In order to provide best control of the regeneration process for each individual patient, the release of protein drugs administered during surgery may need to be timely adapted and/or delayed according to the progress of healing/regeneration. This study aims to establish a multifunctional implant system for a local on-demand release, which is applicable for various types of proteins. It was hypothesized that a tubular multimaterial container kit, which hosts the protein of interest as a solution or gel formulation, would enable on-demand release if equipped with the capacity of diameter reduction upon external stimulation. Using devices from poly(ɛ-caprolactone) networks, it could be demonstrated that a shape-memory effect activated by heat or NIR light enabled on-demand tube shrinkage. The decrease of diameter of these shape-memory tubes (SMT) allowed expelling the payload as demonstrated for several proteins including SDF-1α, a therapeutically relevant chemotactic protein, to achieve e.g. continuous release with a triggered add-on dosing (open tube) or an on-demand onset of bolus or sustained release (sealed tube). Considering the clinical relevance of protein factors in (stem) cell attraction to lesions and the progress in monitoring biomarkers in body fluids, such on-demand release systems may be further explored e.g. in heart, nerve, or bone regeneration in the future., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ensuring an adequate angiogenic response during wound healing is a prevailing clinical challenge in biomaterials science. To address this, we aimed to develop a pro-angiogenic gene-activated scaffold (GAS) that could activate MSCs to produce paracrine factors and influence angiogenesis and wound repair. A non-viral polyethyleneimine (PEI) nanoparticles carrying a gene encoding for stromal derived factor-1 alpha (SDF-1α) was combined with a collagen-chondroitin sulfate scaffold to produce the GAS. The ability of this platform to enhance the angiogenic potential of mesenchymal stem cells (MSCs) was then assessed. We found that the MSCs on GAS exhibited early over-expression of SDF-1α mRNA with the activation of angiogenic markers VEGF and CXCR4. Exposing endothelial cells to conditioned media collected from GAS supported MSCs promoted a 20% increase in viability and 33% increase in tubule formation (p < 0.05). Furthermore, the conditioned media promoted a 50% increase in endothelial cell migration and wound closure (p < 0.005). Gene expression analysis of the endothelial cells revealed that the functional response was associated with up-regulation of angiogenic genes; VEGF, CXCR4, eNOS and SDF-1α. Overall, this study shows collagen-based scaffolds combined with SDF-1α gene therapy can provide enhanced pro-angiogenic response, suggesting a promising approach to overcome poor vasculature during wound healing., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chemokines are known to stimulate directed migration of cancer cells. Therefore, the strategy involving gradual chemokine release from polymeric vehicles for trapping cancer cells is of interest. In this work, the chemokine stromal cell-derived factor-1α (SDF-1α) was encapsulated into nanoparticles composed of poly-(lactic-co-glycolic acid) (PLGA) and a polyethylene glycol (PEG)-PLGA co-polymer to achieve sustained release. SDF-1α, and lysozyme as a model protein, were firstly precipitated to promote their stability upon encapsulation. A novel phase separation method utilising a non-toxic solvent in the form of isosorbide dimethyl ether was developed for the individual encapsulation of SDF-1α and lysozyme precipitates. Uniform nanoparticles of 200-250 nm in size with spherical morphologies were successfully synthesised under mild formulation conditions and conveniently freeze-dried in the presence of hydroxypropyl-β-cyclodextrin as a stabiliser. The effect of PLGA carboxylic acid terminal capping on protein encapsulation efficiency and release rate was also explored. Following optimisation, sustained release of SDF-1α was achieved over a period of 72 h. Importantly, the novel encapsulation process was found to induce negligible protein denaturation. The obtained SDF-1α nanocarriers may be subsequently incorporated within a hydrogel or other scaffolds to establish a chemokine concentration gradient for the trapping of glioblastoma cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Impaired wound closure is a growing medical problem associated with metabolic diseases and aging. Immune cells play important roles in wound healing by following instructions from the microenvironment. Here, we developed a technology to bioengineer the wound microenvironment and enhance healing abilities of the immune cells. This resulted in strongly accelerated wound healing and was achieved by transforming Lactobacilli with a plasmid encoding CXCL12. CXCL12-delivering bacteria administrated topically to wounds in mice efficiently enhanced wound closure by increasing proliferation of dermal cells and macrophages, and led to increased TGF-β expression in macrophages. Bacteria-produced lactic acid reduced the local pH, which inhibited the peptidase CD26 and consequently enhanced the availability of bioactive CXCL12. Importantly, treatment with CXCL12-delivering Lactobacilli also improved wound closure in mice with hyperglycemia or peripheral ischemia, conditions associated with chronic wounds, and in a human skin wound model. Further, initial safety studies demonstrated that the topically applied transformed bacteria exerted effects restricted to the wound, as neither bacteria nor the chemokine produced could be detected in systemic circulation. Development of drugs accelerating wound healing is limited by the proteolytic nature of wounds. Our technology overcomes this by on-site chemokine production and reduced degradation, which together ensure prolonged chemokine bioavailability that instructed local immune cells and enhanced wound healing., Competing Interests: Conflict of interest statement: The technology of transformed Lactobacillus reuteri-producing chemokines is filed for patent protection (PCT/EP2015/081146, WO2016/102660), and drug candidates using this technology are being developed by a company of which E.V., S.R., and M.P. are shareholders., (Copyright © 2018 the Author(s). Published by PNAS.)

Hepatocellular carcinoma develops within an altered mechanical and biochemical environment. The chemokine C-X-C motif chemokine ligand 12 plays an important role in tumor cell metastasis during the process of the epithelial-mesenchymal transition. Here, we successfully engineered a biomimetic matrix made up of polyelectrolyte films with appropriate stiffness, which could present C-X-C motif chemokine ligand 12 in an immobilized status in a spatially controlled manner. The adsorbed amounts of C-X-C motif chemokine ligand 12 could be precisely adjusted over a large range from 27 ng/cm 2 to 2.6 µg/cm 2 . Immobilized C-X-C motif chemokine ligand 12 induced an obvious increase in hepatocellular carcinoma cell adhesion, spreading, and migration in a dose-dependent manner. The phenomenon was associated with proportion changes of three phenotypes of cell morphology (round, polygonal, and elongated) and higher concentrations of immobilized C-X-C motif chemokine ligand 12 led to the rising number of elongated cells along with up-regulation of the mesenchymal markers, as a critical step in epithelial-mesenchymal transition. CD44 and integrin α v β 3 revealed the spatial coincidence in three cell phenotypes. Immobilized C-X-C motif chemokine ligand 12-induced ERK phosphorylation also exhibited dose-dependent manner. Our results highlight that an engineered matrix to locally deliver chemokine exhibits the potential to manipulate important cellular responses (including adhesion, spreading, migration, morphology, distribution of surface receptors, and signaling pathways) in the epithelial-mesenchymal transition process during hepatocellular carcinoma development.

Aims: Inflammation plays a crucial role in aneurysm wall remodeling, which could lead to the rupture of intracranial aneurysms. Stromal cell-derived factor 1α (SDF-1α), a vital inflammation cytokine, is also related to aneurysm pathogenesis. However, the characteristics of SDF-1α expression and its role in aneurysm remodeling remain largely unknown. In this study, we aimed to investigate the expression dynamics of SDF-1α and its correlation with aneurysm remodeling., Methods: Saccular aneurysms were induced by porcine pancreatic elastase in New Zealand White rabbits. Aneurysm size was measured by digital subtraction angiography. Endothelial-like cells on the aneurysm wall were assessed on postoperative days 1, 3, 7, 14, 21, and 30. SDF-1α levels in the aneurysmal wall and serum were examined at several follow-up time points. Adherent molecule expression was examined, and migration assays were performed in vitro. After SDF-1α stimulation, the mobilization of endothelial-lineage cells and its role in the reendothelialization of the aneurysm wall were investigated in a saccular aneurysm rabbit model., Results: After the creation of saccular aneurysms in rabbits, the aneurysm sacs were filled with acute thrombosis within 3days, followed by a significant enlargement on day 14 and maturation on day 21. Serum SDF-1α levels increased in a bimodal fashion on day 1 and day 14, whereas SDF-1α expression in the aneurysm wall reached its maximum on day 14. VE-cadherin was up-regulated after SDF-1α stimulation and down-regulated by the SDF-1α ligand blocker AMD3100. Endothelial progenitor cell migration was enhanced by SDF-1α and blocked by AMD3100. The in vivo administration of SDF-α to rabbits with saccular aneurysms promoted endothelial-lineage cell mobilization into the peripheral blood and reendothelialization of the aneurysm wall., Conclusions: The SDF-1α expression level in the peripheral blood and local aneurysm wall correlated with the aneurysm remodeling process in rabbits with elastase-induced saccular aneurysms. We conclude that SDF-1α may facilitate aneurysm wall remodeling by up-regulating VE-cadherin expression and mobilizing endothelial-lineage cells., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Disappointing results of skeletal muscle precursor cell (skMPC) therapy for women with intrinsic urinary sphincter deficiency (ISD) associated urinary incontinence has increased interest in alternative sphincter regenerative approaches. This study was to measure the safety and efficacy of the cell homing chemokine CXCL12 versus skMPCs in a rat model of ISD. Thirty-six adult female Sprague Dawley rats were divided into 6 treatment (Tx) conditions: (a) no ISD/noTx [Control]; (b) ISD/noTx; (c) ISD + skMPCs; (d) ISD + 3.5 mg CXCL12; (e) ISD + 7mg CXCL12; and (f) ISD + 14 mg CXCL12. Tx's were injected directly into the sphincter complex 30 days post ISD and rats euthanized 30 days post Tx. Blood samples for measurements of kidney and liver function, white and red blood cell counts, were taken at baseline and at euthanasia. Leak point pressures (LPP) were measured prior to, and sphincter collagen/muscle content measured after, euthanasia. There were no effects of treatments on white or red/white blood cell counts, kidney/liver function tests or histopathology of the urinary sphincter complex or surrounding tissues. ISD lowered LPP 35% and sphincter muscle content by 17% versus control rats. CXCL12, but not skMPC injections, restored both LPP to control values in a dose-dependent fashion. Both skMPCs and CXCL12 restored sphincter muscle content to control values. This chemokine approach may represent a novel therapeutic option for ISD and appears, at least short-term, to produce little clinical or tissue pathology. Stem Cells Translational Medicine 2017;6:1740-1746., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Background & Objectives: Next generation transplantation medicine aims to develop stimulating cocktail for increased ex vivo expansion of primitive hematopoietic stem and progenitor cells (HSPC). The present study was done to evaluate the cocktail GF (Thrombopoietin + Stem Cell factor + Flt3-ligand) and homing-defining molecule Stromal cell-derived factor 1 (SDF1) for HSPC ex vivo expansion., Methods: Peripheral blood stem cell (n=74) harvests were analysed for CD34hiCD45lo HSPC. Immunomagnetically enriched HSPC were cultured for eight days and assessed for increase in HSPC, colony forming potential in vitro and in vivo engrafting potential by analyzing human CD45+ cells. Expression profile of genes for homing and stemness were studied using microarray analysis. Expression of adhesion/homing markers were validated by flow cytometry/ confocal microscopy., Results: CD34hiCD45lo HSPC expansion cultures with GF+SDF1 demonstrated increased nucleated cells (n=28, P+ cells (n=8, P=0.021) and increased colony forming units (cfu) compared to unstimulated and GF-stimulated HSPC. NOD-SCID mice transplanted with GF+SDF1-HSPC exhibited successful homing/engraftment (n=24, PInterpretation & conclusions: Cocktail of cytokines and SDF1 showed good potential to successfully expand HSPC which exhibited enhanced ability to generate multilineage cells in short-term and long-term repopulation assay. This cocktail-mediated stem cell expansion has potential to obviate the need for longer and large volume apheresis procedure making it convenient for donors.

Mobilized bone marrow-derived stem cells (BMSC) have been discussed as an alternative strategy for endogenous repair. Thereby, different approaches for BMSC mobilization have been pursued. Herein, the role of a newly discovered oligonucleotide for retinal homing and regeneration capability of BMSCs was investigated in the sodium iodate (NaIO 3 ) model of retinal degeneration. Mobilization was achieved in GFP-chimera with NOX-A12, a CXC-motif chemokine ligand 12 (CXCL12)/stromal cell-derived factor 1 (SDF-1)-neutralizing L-aptamer. BMSC homing was directed by intravitreal SDF-1 injection. Visual acuity was measured using the optokinetic reflex. Paraffin cross sections were stained with hematoxylin and eosin for retinal thickness measurements. Immunohistochemistry was performed to investigate the expression of cell-specific markers after mobilization. A single dose of NOX-A12 induced significant mobilization of GFP + cells which were found in all layers within the degenerating retina. An additional intravitreal injection of SDF-1 increased migration towards the site of injury. Thereby, the number of BMSCs (Sca-1 + ) found in the damaged retina increased whereas a decrease of activated microglia (Iba-1 + ) was found. The mobilization led to significantly increased visual acuity. However, no significant changes in retinal thickness or differentiation towards retinal cell types were detected. Systemic mobilization by a single dose of NOX-A12 showed increased homing of BMSCs into the degenerated retina, which was associated with improved visual function when injection of SDF-1 was additionally performed. The redistribution of the cells to the site of injury combined with their observed beneficial effects support the endogenous therapeutic strategy for retinal repair.

Recruiting neural stem cell (NSC) at the lesion site is essential for central nervous system repair. This process could be triggered by the local delivery of the chemokine SDF-1. We compared two PLGA formulations for local brain SDF-1 delivery: SDF-1 loaded microspheres (MS) and SDF-1 loaded nanoparticles (NP). Both formulations were able to encapsulate more than 80% of SDF-1 but presented different release profiles, with 100% of SDF-1 released after 6days for the MS and with 25% of SDF-1 released after 2 weeks for NP. SDF-1 bioactivity was demonstrated by a chemotactic assay. When injected in mouse brain after traumatic brain injury, only SDF-1 nanoparticles induced NSC migration to the damage area. More neuroblasts (DCX+ cells) could be visualized around the lesions treated with NP SDF-1 compared to the other conditions. Rostral migratory stream destabilization with massive migration of DCX+ cell toward the perilesional area was observed 2 weeks after NP SDF-1 injection. Local injection of SDF-1-loaded nanoparticles induces recruitment of NSC and could be promising for brain injury lesion., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Reendothelialization in the aneurysm neck is pivotal to vascular repair for intracranial aneurysm after flow diverter (FD) implantation. Recombinant human stromal cell-derived factor 1α (rhSDF-1α) is a vital chemoattractant to stem cells and potentially facilitates reendothelialization. Here, we sought to investigate the therapeutic effects of intravenous administration of rhSDF-1α and uncover its potential mechanism for promoting aneurysm neck reendothelialization. Recombinant pET32a-186 plasmid was transformed into Escherichia coli to produce the rhSDF-1α protein with biological activity. FD was implanted into the elastase-induced saccular aneurysm in New Zealand white rabbits. rhSDF-1α (50 μg/kg/day) was intravenously administrated for consecutive 7 days after FD implantation. After these procedures, aneurysms were harvested after 2 or 4 weeks. Scanning electron microscopy was used to measure the neointima thickness and count the endothelial-like cells at aneurysm neck. Four weeks later, the mRNA levels of endothelial markers in the neointima at aneurysm neck were examined. Migration assay showed that rhSDF-1α could induce migration of endothelial progenitor cells in a dose-dependent manner. Two weeks after stent implantation, follow-up angiography showed partial aneurysm occlusion in one of each group and total aneurysm occlusion in 17 saccular aneurysm rabbits (9 of the rhSDF-1α group and 8 of the control group). No significant change of neointima thickness at aneurysm neck was observed. Intriguingly, more endothelial-like cells were observed at aneurysm neck in the rhSDF-1α group at 2 weeks (55 vs 13 cells per high-power field) and 4 weeks (104 vs 60 cells per high-power field). The mRNA levels of Tie-2, VE-cadherin, KDR and E-selectin were significantly enhanced compared with those of the control group. These results showed that intravenous administration of rhSDF-1α can accelerate reendothelialization in the aneurysm neck after FD implantation. Our study reveals an important role of rhSDF-1α in inducing aneurysm occlusion and suggests that it achieves its function through modulating the reendothelialization., (© The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Evidence has shown that stromal cell-derived factor (SDF-1/CXCL12) plays an important role in maintaining adult neural progenitor cells (NPCs). SDF-1 is also known to enhance recovery by recruiting NPCs to damaged regions and recent studies have revealed that SDF-1α exhibits pleiotropism, thereby differentially affecting NPC subpopulations. In this study, we investigated the role of SDF-1 in in vitro NPC self-renewal, proliferation and differentiation, following treatment with different concentrations of SDF-1 or a CXCR4 antagonist, AMD3100. We observed that AMD3100 inhibited the formation of primary neurospheres. However, SDF-1 and AMD3100 exhibited no effect on proliferation upon inclusion of growth factors in the media. Following growth factor withdrawal, AMD3100 and SDF-1 treatment resulted in differential effects on NPC proliferation. SDF-1, at a concentration of 500ng/ml, resulted in an increase in the relative proportion of oligodendrocytes following growth factor withdrawal-induced differentiation. Using CXCR4 knockout mice, we observed that SDF-1 affected NPC proliferation in the sub-ventricular zone (SVZ). We also investigated the occurrence of differential CXCR4 expression at different stages during lineage progression. These results clearly indicate that signaling interactions between SDF-1 and CXCR4 play an important role in adult SVZ lineage cell proliferation and differentiation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Stromal cell-derived factor-1 (SDF-1) is a cytokine that is important in stem and progenitor cell recruitment in tissue repair after injury. Regenerative procedures using collagen membranes (CMs) are presently well established in periodontal and implant dentistry. The objective of this study is to test the subsequent effects of the released SDF-1 from a CM on bone regeneration compared to platelet-derived growth factor (PDGF) in vitro and in vivo. For in vitro studies, cell proliferation, alkaline phosphatase activity, and osteoblastic differentiation marker genes were assessed after MC3T3-E1 mouse preosteoblasts were cultured with CMs containing factors. In vivo effects were investigated by placement of CMs containing SDF-1 or PDGF using a rat mandibular bone defect model. At 4 weeks after the surgery, the new bone formation was measured using micro-computed tomography (µCT) and histological analysis. The results of in vitro studies revealed that CM delivery of SDF-1 significantly induced cell proliferation, ALP activity, and gene expression of all osteogenic markers compared to the CM alone or control, similar to PDGF. Quantitative and qualitative µCT analysis for volume of new bone formation and the percentage of new bone area showed that SDF-1-treated groups significantly increased and accelerated bone regeneration compared to control and CM alone. The enhancement of bone formation in SDF-1-treated animals was dose-dependent and with levels similar to those measured with PDGF. These results suggest that a CM with SDF-1 may be a great candidate for growth factor delivery that could be a substitute for PDGF in clinical procedures where bone regeneration is necessary.

In this study, a cell-free bone tissue engineering system based on a silk fibroin (SF)/nano-hydroxyapatite (nHAp) scaffold was developed, in which two bioactive molecules, stromal cell derived factor-1 (SDF-1) and bone morphogenetic protein-2 (BMP-2), were embedded and released in a sequential and controlled manner to facilitate cell recruitment and bone formation, respectively. BMP-2 was initially loaded into SF microspheres, and these BMP-2 containing microspheres were subsequently encapsulated into the SF/nHAp scaffolds, which were successively functionalized with SDF-1 via physical adsorption. The results indicated rapid initial release of SDF-1 during the first few days, followed by slow and sustained release of BMP-2 for as long as three weeks. The composite scaffold significantly promoted the recruitment of bone marrow mesenchymal stem cells (BMSCs) and osteogenic differentiation of them in vitro. Further, the in vivo studies using D-Luciferin-labeled BMSCs indicated that implantation of this composite scaffold markedly promoted the recruitment of BMSCs to the implanted sites. Enhanced bone regeneration was identified at 12 weeks' post-implantation. Taken together, our findings suggested that the sequential and sustained release of SDF-1 and BMP-2 from the SF/nHAp scaffolds resulted in a synergistic effect on bone regeneration. Such a composite system, therefore, shows promising potential for cell-free bone tissue engineering applications., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Homing of endothelial progenitor cells (EPC) to the ischemic tissues is a key event in neovascularization and tissue regeneration. In response to ischemic insult, injured tissues secrete several chemo-cytokines, including stromal cell-derived factor-1α (SDF-1α), which triggers mobilization and homing of bone marrow-derived EPC (BMD-EPC). We previously reported that SDF-1α-induced EPC homing is mediated by a panel of adhesion molecules highly or selectively expressed on the activated endothelium in ischemic tissues, including E-selectin. Elevated E-selectin on wound vasculature serve as docking sites for circulating EPC, which express counterpart E-selectin ligands. Here, we show that SDF-1α presented in wound tissue and released into circulation can act both locally and remotely to induce ischemic tissue endothelium and BMD-EPC to express both E-selectin and its ligands. By performing BM transplantation using E-selectin -/- and E-selectin +/+ mice as the donors and recipients respectively, we demonstrate that upregulated dual E-selectin/ligand pairs reciprocally expressed on ischemic tissue endothelium and BMD-EPC act as double-locks to secure targeted EPC- endothelium interactions by which to facilitate EPC homing and promote neovascularization and tissue repair. These findings describe a novel mechanism for BMD-EPC homing and indicate that dual E-selectin/ligand pairs may be effective targets/tools for therapeutic neovascularization and targeted cell delivery.

Background: Despite promising therapeutic innovation over the last decade, peripheral arterial disease remains a prevalent morbidity, as many patients are still challenged with peripheral ischemia. We hypothesized that delivery of engineered stromal cell-derived factor 1-alpha (ESA) in an ischemic hind limb will yield significant improvement in perfusion., Methods: Male rats underwent right femoral artery ligation, and animals were randomized to receive a 100 μL injection of saline (n = 9) or 6 μg/kg dosage of equal volume of ESA (n = 12) into the ipsilateral quadriceps muscle. Both groups of animals were also given an intraperitoneal injection of 40 μg/kg of granulocyte macrophage colony-stimulating factor (GMCSF). Perfusion was quantified using a laser Doppler imaging device preoperatively, and on postoperative days 0, 7, and 14. Immunohistochemistry was performed to quantify angiogenesis on day 14, and an mRNA profile was evaluated for angiogenic and inflammatory markers., Results: Compared with the saline/GMCSF group at day 14, the ESA/GMCSF-injected animals had greater reperfusion ratios (Saline/GMCSF, 0.600 ± 0.140 vs ESA/GMCSF, 0.900 ± 0.181; group effect P = .006; time effect P < .0001; group×time effect P < .0001), elevated capillary density (10×; Saline/GMCSF, 6.40 ± 2.01 vs ESA/GMCSF, 18.55 ± 5.30; P < .01), and increased mRNA levels of vascular endothelial growth factor-A (Saline/GMCSF [n = 6], 0.298 ± 0.205 vs ESA/GMCSF [n = 8], 0.456 ± 0.139; P = .03)., Conclusions: Delivery of ESA significantly improves perfusion in a rat model of peripheral arterial disease via improved neovasculogenesis, a finding which may prove beneficial in the treatment strategy for this debilitating disease., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Triggering of the early healing events, including the recruitment of progenitor cells, has been suggested to promote bone regeneration. In implantology, local drug release technologies could provide an attractive approach to promote tissue regeneration. In this study, we targeted the chemotactic SDF-1α/CXCR4 axis that is responsible e.g. for the homing of stem cells to trauma sites. This was achieved by local delivery of plerixafor, an antagonist to CXCR4, and/or SDF-1α, from titanium implants coated with mesoporous titania thin films with a pore size of 7.5 nm. In vitro drug delivery experiments demonstrated that the mesoporous coating provided a high drug loading capacity and controlled release. The subsequent in vivo study in rat tibia showed beneficial effects with respect to bone-implant anchorage and bone-formation along the surface of the implants when plerixafor and SDF-1α were delivered locally. The effect was most prominent by the finding that the combination of the drugs significantly improved the mechanical bone anchorage. These observations suggest that titanium implants with local delivery of drugs for enhanced local recruitment of progenitor cells have the ability to promote osseointegration. This approach may provide a potential strategy for the development of novel implant treatments. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2466-2475, 2016., (© 2016 Wiley Periodicals, Inc.)

Diabetic foot ulcers (DFUs) are a severe complication of diabetes mellitus. Altered cell migration due to microcirculatory deficiencies as well as excessive and prolonged reactive oxygen species production are implicated in the delayed healing of DFUs. The goal of this research was to assess whether sustained release of SDF-1, a chemokine that promotes endothelial progenitor cell homing and angiogenesis, from a citrate-based antioxidant thermoresponsive polymer would significantly improve impaired dermal wound healing in diabetes. Poly (polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) was synthesized via sequential polycondensation and free radical polymerization reactions. SDF-1 was entrapped via gelation of the PPCN+SDF-1 solution above its lower critical solution temperature (LCST) and its release and bioactivity was measured. The effect of sustained release of SDF-1 from PPCN (PPCN+SDF-1) versus a bolus application of SDF-1 in phosphate buffered saline (PBS) on wound healing was evaluated in a diabetic murine splinted excisional dermal wound model using gross observation, histology, immunohistochemistry, and optical coherence tomography microangiography. Increasing PPCN concentration decreased SDF-1 release rate. The time to 50% wound closure was 11days, 16days, 14days, and 17days for wounds treated with PPCN+SDF-1, SDF-1 only, PPCN only, and PBS, respectively. Wounds treated with PPCN+SDF-1 had the shortest time for complete healing (24days) and exhibited accelerated granulation tissue production, epithelial maturation, and the highest density of perfused blood vessels. In conclusion, sustained release of SDF-1 from PPCN is a promising and easy to use therapeutic strategy to improve the treatment of chronic non-healing DFUs., (Copyright © 2016 Elsevier B.V. All rights reserved.)