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Background: The super-thin skin flap formed by skin and soft tissue expansion has large area and good ductility, so it can be used to repair skin defects. However, because the flap is thin, the blood flow in the dermis of the super-thin expanded flap is weakened, and flap rupture and necrosis after secondary flap transfer may occur., Objective: To compare the skin thickness difference between the expanded ultrathin flaps injected with concentrated growth factor (CGF) and the blank group or saline group., Methods: From June 2021 to December 2023, 10 patients (44 sites) with large-area scars or skin tumors were treated, and a single center half randomized controlled trial was conducted. The test site of expander implantation was divided into three groups: intradermal injection of CGF group, normal saline group and blank group. The same amount of expansion was performed every 1-2 weeks, and CGF or normal saline was injected into the dermis every 4 weeks, a total of three times. After 2-3 months of expansion, color Doppler ultrasound was used to measure the skin thickness of each group., Results: Compared with the blank group, the skin thickness of CGF group was 1.75 ± 0.08 mm, and that of BLA blank group was 1.42 ± 0.07 mm, with statistically significant difference (p < 0.0001); In the other group, compared with the saline group, the skin thickness of the CGF group was 1.54 ± 0.08 mm, and the average skin thickness of the saline group was 1.40 ± 0.08 mm, with significant difference between the two groups (p = 0.0067)., Conclusion: CGF intradermal injection can increase the skin thickness of super-thin skin flap in the process of soft tissue expansion, which is a safe and effective auxiliary method of skin expansion., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Chemerin is an adipokine that contributes to metabolism regulation. Nucleus tractus solitarius (NTS) is the first relay station in the brain for accepting various visceral afferent activities for regulating cardiovascular activity. However, the roles of chemerin in the NTS in regulating sympathetic activity and blood pressure are almost unknown. This study aimed to determine the role and potential mechanism of chemerin in the NTS in modulating sympathetic outflow and blood pressure. Bilateral NTS microinjections were performed in anaesthetized adult male Sprague-Dawley rats. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were highly expressed in caudal NTS (cNTS). Microinjection of chemerin-9 to the cNTS increased RSNA, MAP and HR, which were prevented by CMKLR1 antagonist α-NETA, superoxide scavenger tempol or N-acetyl cysteine, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium or apocynin. Chemerin-9 increased superoxide production and NADPH oxidase activity in the cNTS. The increased superoxide production induced by chemerin-9 was inhibited by α-NETA. The effects of cNTS microinjection of chemerin-9 on the RSNA, MAP and HR were attenuated by the pretreatment with paraventricular nucleus (PVN) microinjection of NMDA receptor antagonist MK-801 rather than AMPA/kainate receptor antagonist CNQX. These results indicate that chemerin-9 in the NTS increases sympathetic outflow, blood pressure and HR via CMKLR1-mediated NADPH oxidase activation and subsequent superoxide production in anaesthetized normotensive rats. Glutamatergic inputs in the PVN are needed for the chemerin-9-induced responses., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The corpus luteum (CL) is a temporary endocrine gland that synthesizes progesterone. The luteal progesterone plays a central role in the regulation of the estrous cycle as well as the implantation and maintenance of pregnancy. Our previous study showed the expression of adropin and its receptor, GPR19, in the luteal cells and its significant role in luteinization. The aim of the present study was to investigate the in vitro effect of adropin on hCG-induced ovarian functions in adult mice. We also evaluated the effect of exogenous treatment with adropin on ovarian steroidogenesis and anti-oxidant parameters, with special emphasis on CL function. Our results demonstrated that adropin acts synergistically with hCG to promote ovarian steroidogenesis and survival by increasing the expression of StAR, 3β-HSD, and aromatase proteins and decreasing the BAX/BCL2 ratio. Exogenous adropin treatment increased progesterone production by increasing the expression of GPR19, StAR and 3β-HSD enzymes in the mouse ovary. Also, adropin inhibited the luteal oxidative stress by increasing nuclear translocation of NRF-2 in CL, which resulted in increased HO-1 expression and SOD, catalase activity. Decreased oxidative stress might inhibit the translocation of NF-κB into the nucleus of luteal cells, resulting into increased survival and decreased apoptosis, as evident by decreased lipid peroxidation, BAX/BCL2 ratio, caspase 3, active caspase 3 expression, and TUNEL-positive cells in adropin treated mice. Our findings suggest that adropin can be a promising candidate that can enhance the survivability of the CL., Competing Interests: Declaration of Competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple Food and Drug Administration-approved Ca V 2.2 modulators available for the treatment of pain. Although effective, drugs targeting Ca V 2.2 are complicated by the same obstacles facing other pain therapeutics-invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of Ca V 2.2 channels, collapsin response mediator protein 2, that allows us to indirectly regulate Ca V 2.2 expression and function. We previously developed a peptidomimetic modulator of collapsin response mediator protein 2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of Ca V 2.2. The potent analgesic properties of CBD3063, combined with the lack of negative side effects, prompted us to assess the efficacy of CBD3063 in a rodent model of OA pain. Here, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and nonevoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest that CBD3063 is an effective analgesic for OA pain. PERSPECTIVE: Despite the high prevalence of OA pain worldwide, current treatment options remain limited. We demonstrate that CBD3063-mediated disruption of the Ca V 2.2-collapsin response mediator protein 2 interaction alleviates pain in a preclinical joint pain model, providing a promising basis for the development of new OA pain treatments., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Impaired wound healing due to insufficient cell proliferation and angiogenesis is a significant physical and psychological burden to patients worldwide. Therapeutic delivery of exogenous growth factors (GFs) at high doses for wound repair is non-ideal as GFs have poor stability in proteolytic wound environments. Here, we present a two-stage strategy using bioactive sucralfate-based microneedle (SUC-MN) for delivering interleukin-4 (IL-4) to accelerate wound healing. In the first stage, SUC-MN synergistically enhanced the effect of IL-4 through more potent reprogramming of pro-regenerative M2-like macrophages via the JAK-STAT pathway to increase endogenous GF production. In the second stage, sucralfate binds to GFs and sterically disfavors protease degradation to increase bioavailability of GFs. The IL-4/SUC-MN technology accelerated wound healing by 56.6 % and 46.5 % in diabetic mice wounds and porcine wounds compared to their respective untreated controls. Overall, our findings highlight the innovative use of molecular simulations to identify bioactive ingredients and their incorporation into microneedles for promoting wound healing through multiple synergistic mechanisms., 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 Ltd. All rights reserved.)

Purpose: To answer the following question: 'Do recombinant, purified, and concentrated growth factors enhance the regenerative potential of particulate bone graft substitutes in maxillary sinus floor augmentation (MSA)?', Materials and Methods: Human studies comparing histomorphometric data on new bone formation, residual graft material, and fibrous tissue ratio (outcomes of interest) following MSA procedures employing particulate bone grafts/substitutes in combination or not with growth factors were retrieved from PubMed/MEDLINE, Web of Science, Cochrane, and Scopus online databases and complemented with a hand search. Controlled studies published in English up to December 2022 and reporting on histomorphometric data expressed as volume percentage of the outcomes of interest were considered. Risk of bias was assessed, and a meta-analysis was performed to investigate the effects of supplementary growth factors on new bone formation, remaining graft particles, and fibrous tissue ratio., Results: Data were included from 613 samples in 477 patients reported in 22 publications. Meta-analysis showed that platelet-rich plasma or platelet-rich fibrin resulted in 49% more new bone formation than in control group areas (P &#61; .004), and those areas supplemented with growth factors presented 57% less residual graft particles after healing (P < .0001). A significant (P &#61; .03) 1.85-fold increase in connective tissue formation was noted in areas treated with recombinant human bone morphogenetic proteins (rhBMPs) after healing., Conclusions: Selective supplementary growth factors may enhance new bone formation and accelerate particulate graft turnover, while rhBMP may significantly increase connective tissue formation in MSA procedures in humans.

Context: Diabetes mellitus is associated with morbid complications such as diabetic foot ulcers (DFUs) that may lead to amputations or mortality if not managed adequately., Objective: New adjunctive interventions to treat diabetic wounds include topical biologics and growth factors. This study aims to evaluate their efficacy in improving wound-healing outcomes and safety., Methods: Comprehensive database searches of MEDLINE via PubMed, EMBASE, and Cochrane were performed from inception to December 2022. Three independent researchers selected the studies. Randomized controlled trials that compared the use of a topical biologic growth factor-containing regimen to other biologics or standard of care (SOC) were included. This review followed PRISMA guidelines. Risk of bias analysis was performed using the Jadad scale. Network meta-analysis was performed. Treatments were grouped into common nodes based on the type of biologic agent. Primary outcomes of interest were healing rate and time to wound closure. Secondary outcomes included wound infection, serious adverse events (AEs), and amputation rate., Results: Human umbilical cord (HUC) was associated with the highest cure, followed by recombinant human epidermal growth factor (hEGF). A significantly greater reduction in the time to cure DFUs was seen in HUC, hEGF, and fibroblast growth factor (FGF). There was a significantly lower risk of AEs when platelet-rich plasma (PRP) was administered., Conclusion: HUC, hEGF, and FGF are promising topical biologics with statistically significant primary outcomes compared to SOC, while PRP is effective in reducing ulcer-related AEs. HUC has been found to be the most effective in terms of cure rate and a reduction in time to cure., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Concentrated growth factor (CGF) injection has proven effective in treating androgenetic alopecia (AGA). The primary mechanism of CGF in treating AGA is thought to be the CD34+ stem cells and platelets-associated growth factors being injected into the scalp. CGF efficacy in treating AGA may rely on the activation level of these stem cells and platelets. The 640 nm laser is a United States Food and Drug Administration approved AGA treatment that activates follicle stem cells. Therefore, we hypothesize that pretreating CGF with a 640 nm laser may further activate CD34+ stem cells and platelets, thereby improving the efficacy of CGF in treating AGA., Objective: This study aims to investigate whether 640 nm laser pretreated CGF (640CGF) has a greater effect in treating AGA than 640 nm laser non-pretreated CGF (N640CGF) and evaluate whether 640 nm laser pretreatment changed CD34+ cell percentage., Methods: This study enrolled 10 patients (8 male, 2 female) with AGA aged 18-60 years who received CGF injections. The 640CGF group was pretreated with a 640 nm laser at an energy density of 4 J/cm 2 , with a 30 cm irradiation distance for 30 min. Half of the scalp was treated with 640CGF, whereas the other half was treated with N640CGF. The injection was prepared by a doctor who did not know which blood tube had been pretreated. The treatment efficacy was evaluated using a trichoscope 1 month after injection., Results: All 10 (100%) patients participated in the follow-up visit, and a higher quantity of new hairs was observed on the side injected with 640CGF than N640CGF (p = 0.019). Additionally, fewer malnourished hairs were observed on the 640CGF pretreated side (p = 0.015). No serious adverse events were reported., Conclusions: A higher percentage of CD34+ stem cells and improved efficacy in AGA treatment could be observed with CGF prepared from 640 nm laser-pretreated blood., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Objective: We will perform the systematic review to evaluate the effect of applying concentrated growth factor (CGF) on relieving postoperative complications and promoting wound healing following mandibular third molar extraction., Methods: The PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Biology Medicine Disc (CBM), and VIP Databases will be comprehensively searched up to May 31, 2024. Randomized controlled trials (RCTs) examining the application of CGF after mandibular third molar extraction will be included. The protocol was registered in PROSPERO, and the registration ID was CRD42023463234. Two reviewers will conduct the literature search, eligible study selection, data extraction, and bias risk assessment (using the Cochrane Risk of Bias 2.0 tool). Data analysis will be performed with RevMan software (version 5.4)., Results: The results of this study will be available in a peer-reviewed journal., Conclusion: Our study will provide scientific evidence regarding the efficacy of applying CGF in mandibular third molar extraction., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Meniscus tears in the avascular region undergoing partial or full meniscectomy lead to knee osteoarthritis and concurrent lifestyle hindrances in the young and aged alike. Here they reported ingenious photo-polymerizable autologous growth factor loaded 3D printed scaffolds to potentially treat meniscal defects . A shear-thinning photo-crosslinkable silk fibroin methacrylate-gelatin methacrylate-polyethylene glycol dimethacrylate biomaterial-ink is formulated and loaded with freeze-dried growth factor rich plasma (GFRP) . The biomaterial-ink exhibits optimal rheological properties and shape fidelity for 3D printing. Initial evaluation revealed that the 3D printed scaffolds mimic mechanical characteristics of meniscus, possess favourable porosity and swelling characteristics, and demonstrate sustained GFRP release. GFRP laden 3D scaffolds are screened with human neo-natal stem cells in vitro and biomaterial-ink comprising of 25 mg mL -1 of GFRP (GFRP25) is found to be amicable for meniscus tissue engineering. GFRP25 ink demonstrated rigorous rheological compliance, and printed constructs demonstrated long term degradability (>6 weeks), GFRP release (>5 weeks), and mechanical durability (3 weeks). GFRP25 scaffolds aided in proliferation of seeded human neo-natal stem cellsand their meniscus-specific fibrochondrogenic differentiation . GFRP25 constructs show amenable inflammatory response in vitro and in vivo. GFRP25 biomaterial-ink and printed GFRP25 scaffolds could be potential patient-specific treatment modalities for meniscal defects., (© 2024 Wiley‐VCH GmbH.)

Introduction: Cardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation and the propagation of action potentials, ultimately promoting cardiac contractility. This study aimed to investigate the effects of apelin-13 in reversing cardiac suppression induced by bupivacaine in rats., Methods: A rat model of cardiac suppression was established by a 3-min continuous intravenous infusion of bupivacaine at the rate of 5 mg.kg -1 .min -1 , and serial doses of apelin-13 (50, 150 and 450 μg.kg -1 ) were administered to rescue cardiac suppression to identify its dose-response relationship. We used F13A, an inhibitor of Angiotensin Receptor-Like 1 (APJ), and Protein Kinase C (PKC) inhibitor chelerythrine to reverse the effects of apelin-13. Moreover, the protein expressions of PKC, Nav1.5, and APJ in ventricular tissues were measured using Western blotting and immunofluorescence assay., Results: Compared to the control rats, the rats subjected to continuous intravenous administration of bupivacaine had impaired hemodynamic stability. Administration of apelin-13, in a dose-dependent manner, significantly improved hemodynamic parameters in rats with bupivacaine-induced cardiac suppression (p < 0.05), and apelin-13 treatment also significantly upregulated the protein expressions of p-PKC and Nav1.5 (p < 0.05), these effects were abrogated by F13A or chelerythrine (p < 0.05)., Conclusion: Exogenous apelin-13, at least in part, activates the PKC signaling pathway through the apelin/APJ system to improve cardiac function in a rat model of bupivacaine-induced cardiac suppression., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024 Sociedade Brasileira de Anestesiologia. Published by Elsevier España S.L.U. All rights reserved.)

Background: Vascular endothelial growth factor (VEGF)-A, the most abundant subtype of the VEGF family in the eye, plays an important role in corneal homeostasis due to its ability to mediate corneal nerve repair. Repeated intravitreal anti-VEGF injections were shown to significantly reduce corneal nerve density, which might negatively affect corneal homeostasis and lead to a neuropathic dry eye disease. Currently, there are two effective modalities to treat dry eye while supplying VEGF to the ocular surface: serum eye drops (SED) and eye drops manufactured from plasma rich in growth factors (PRGF). The purpose of this study was to measure the VEGF-A concentration in SED and PRGF eye drops., Material and Methods: Ten healthy volunteers donated blood on two separate occasions, 2 - 8 days apart. Thus, a total of 20 blood samples were processed to obtain both SED and PRGF. Concentrations of VEGF-A were quantified by a Simple Plex platform run in triplicate., Results: The VEGF-A concentration in SED and PRGF was very similar between the two blood samples drawn from one individual donor but showed substantial interindividual variability. However, in all 20 samples, VEGF concentrations were substantially higher in SED samples (mean 238.7 ± 146.6 pg/mL) compared to PRGF samples (mean 67.4 ± 46.3 pg/mL). Based upon the analysis of variance (ANOVA) model for the measured concentrations with fixed effects for specimen (SED vs. PRGF) and subject, the mean difference between the SED and PRGF concentration was 168.1 pg/mL (95% confidence interval: [142.4, 193.9], p < 0.001)., Conclusion: Our study showed that the VEGF concentration was higher in SED than in PRGF. This is an important finding, particularly for potential treatment of dry eye disease in patients with neuropathic eye disease, especially in patients that received repeated anti-VEGF intravitreal injections, or in patients with Sjögren's disease, where the level of VEGF in tears might be pathologically decreased. Hypothetically, VEGF might be needed to restore ocular surface homeostasis. Although growing evidence has shown that VEGF-A plays an important role in corneal homeostasis, only a randomized prospective clinical trial will show whether supplying VEGF-A to the ocular surface might successfully restore the corneal homeostasis and overcome the problem of corneal neuropathy in these patients. For such a trial, based on our results, an undiluted SED should be preferred over a PRGF due to the higher content of VEGF-A., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Intradermal administration of QR678 Neo ® hair re-growth factor formulation has already proven its effectiveness and safety in treating androgenetic alopecia and female pattern hair loss., Aim: This study aims to evaluate effectiveness and safety of hair re-growth factor formulation at multiple centers for reduction of hair fall and regrowth of hair in androgenetic alopecia and female pattern hair loss., Materials and Methods: An open-label, prospective, and interventional study was carried out at multiple centers of different countries. A total of 2428 patients with androgenetic alopecia and female pattern hair loss within the age range of 18-65 years were included in the study. Hair pull test, global photographic assessment, videomicroscopic assessment tests were performed at the beginning, after fourth and eighth sessions, and self-assessment through questionnaire related to satisfaction and side effects was carried out at beginning and at after eight session., Results: Hair pull test was positive in only 12% of the patients after eight sessions. Beneficial results were noted in the global assessment score (mean-6) after fourth session and eighth session (mean-8). Huge improvement was noted in terminal hair count, vellus hair count, and hair density after eighth sessions. Also, with self-assessment score, a higher satisfaction score was noted. On long-term follow-up as well, no side effects were noted., Conclusion: Intradermal administration of QR678 Neo ® is an innovative, efficacious, and safe technique for the treatment of androgenetic alopecia and female pattern hair loss., (© 2021 Wiley Periodicals LLC.)

Recent evidence suggests that modulation of the large-conductance, calcium-activated potassium (BK) channel regulates auditory processing in the brain. Because ion channel expression often changes during aging, this could be a factor in age-related hearing loss. The current study explored how the novel BK channel modulator LS3 shapes central auditory processing in young and old adult mice. In vivo extracellular recordings in the auditory midbrain demonstrated that LS3 differentially modulates neural processing along the tonotopic axis. Though sound-evoked activity was reduced in the mid and ventral tonotopic regions, LS3 enhanced excitatory drive and sound-evoked responses for some neurons in the dorsal, low-frequency region. Behavioral assessment using acoustic reflex modification audiometry indicated improved tone salience following systemic LS3 administration. Moderation of these responses with aging correlated with an age-related decline in BK channel expression. These findings suggest that targeting the BK channel enhances responsivity to tonal sounds, providing the potential to improve hearing acuity and treat hearing loss., (Copyright © 2021. Published by Elsevier Inc.)

Efficient bone reconstruction after bone injury remains a great challenge. Injectable supramolecular hydrogels based on amphiphilic peptide have been widely used due to their good biocompatability, non-immunogenicity, and manipulable physicochemical properties by sequence design. Herein, we used a well-studied hydrogelator, NapFFY, to coassemble with osteogenic growth peptide (OGP) to prepare a supramolecular hydrogel, NapFFY-OGP. Both in vitro and in vivo studies demonstrate that OGP was ideally synchronously, and continuously released from the hydrogel to effectively promote the regeneration and reconstruction of skull bone defects. More specifically, after the embedding the rat skull defect area with NapFFY-OGP hydrogels, a bone regeneration rate of 37.54% bone volume fraction (BV/TV) was achieved compared to that of NapFFY hydrogel group (25.09%). NapFFY-OGP hydrogel shows great promise in the clinic repair of bone defects in the future., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hair follicle regeneration has been successful in mice but failed in human being for years. Dermal papilla cells, a specialized mesenchymal stem cell derived from dermal papilla within hair follicles, is considered the key cells for hair follicle regeneration function as both regeneration initiator and regulator. Injectable platelet rich fibrin (i-PRF), a novel biomaterial rich in a variety of growth factors and three-dimensional scaffolds, has shown promising effects on tissue regeneration. In this study, we aimed to evaluate the application of i-PRF in human hair follicle regeneration by examining the biological effects of i-PRF on human dermal papilla cells (hDPCs). Biomaterial compatibility, cell viability, proliferation, migration, alkaline phosphatase activity and trichogenic inductivity were assessed after exposing hDPCs to different concentrations of i-PRF extracts. In addition, we investigated the ultrastructure of i-PRF with all cell components filtered. The results revealed that i-PRF possessing excellent biocompatibility and could significantly promote hDPCs proliferation, migration, and trichogenic inductivity. Furthermore, the concentration of i-PRF is able to remarkably influence hDPCs behavior in a dose-dependent pattern. Different concentrations exhibited differential effects on hDPCs behavior. In general, lower concentration promotes cell proliferation better than higher concentration, while higher concentration promotes cell function better reversely. Best concentration for hDPCs in vitro expending is 1% concentration. 20% concentration is optimal for hair follicle regeneration. In summary, our findings concluded that i-PRF facilitates hair follicle regeneration by promoting human dermal papilla cell proliferation, migration, and trichogenic inductivity., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

We developed an injectable hydrogel system with a sustained release of TGF-β3 through growth factor-loaded microsphere to mimic the cartilage-like microenvironment. Poly(lactic-co-glycolic acid) (PLGA) microspheres incorporated in three dimensional (3D) scaffolds were chosen because of its regulatory approval, good biodegradability, and acting as carriers with sustained release behavior. We evaluated sustained release of TGF-β3 by PLGA microspheres encapsulated in methoxy poly(ethylene glycol)-poly(alanine) (mPA) hydrogels and the resulting enhanced chondrogenic effects. We reported here the effect of the proposed system for sustained release of growth factors on chondrogenesis in cartilage regeneration. PLGA microspheres were used in our thermosensitive mPA hydrogel system with bovine serum albumin as a stabilizing and protecting agent for the emulsion and TGF-β3 enabling sustained release. Gelation, structural properties, and in-vitro release of this composite, that is, microspheres in hydrogel, system were investigated. Using PLGA microspheres to carry growth factors could complement the mPA hydrogel's ability to provide an excellent 3D microenvironment for the promotion of chondrogenic phenotype as compared the systems using mPA hydrogel or microspheres alone. Our study demonstrated that this synthesized composite hydrogel system is capable of modulating the biosynthetic and differentiation activities of chondrocytes. The sustained release of TGF-β3 in this novel hydrogel system could improve biomedical applicability of mPEG-polypeptide scaffolds. The distinctive local growth factor delivery system successfully combined the use of both polymers to be a suitable candidate for prolonged articular cartilage regeneration., (© 2021 Wiley Periodicals LLC.)

Purpose: The aim of the present prospective study was to evaluate the effect of titanium mesh and concentrated growth factor (CGF) membranes in reconstructing severe labial bone defects during immediate implantation of anterior maxillary tooth., Methods: Patients with severe defects presenting on the anterior labial bone plate of maxillary were enrolled in this study. During immediate implantation, the titanium mesh was used to maintain the space of bone graft, collagen membrane, and xenograft bone that were used to guide bone regeneration (GBR). Cone beam computed tomography (CBCT) was used to measure the height and the labial bone thickness around the implant at the time of the second stage surgery, 6 months, 1 year, and 2 years after restoration. The pink esthetic score (PES) was used to evaluate the esthetic outcomes after restoration., Results: 18 patients were enrolled in this study. The survival rate of implants was 100%, and no complication was observed, except for 1 case of titanium mesh exposure which did not affect osteogenesis. In the second stage of surgery, the labial bone was completely reconstructed, and the top of the implant was covered with a small amount of new bone. The thickness of the labial bone was 3.01 mm (±0.23), 2.96 mm (±0.21), 2.93 mm (±0.19), and 2.92 mm (±0.16) at the time of the second stage surgery, 6 months, 1 year, and 2 years after restoration, respectively. The height of the marginal bone around implants was above the top of implant at the time of the second stage surgery and then reduced 0.72 mm (±0.07), 0.91 mm (±0.08), and 0.90 mm (±0.07) at the time point of 6 months, 1 year, and 2 years after restoration, respectively. The changes of bone thickness and height were statistically significant within one year, but stable after one year. The PES values showed the same tendency., Conclusions: With the limitation of the present prospective study, the combination of titanium mesh and CGF membrane could provide space maintenance for bone augmentation of alveolar bone defects and improve the bone regeneration in patients with severe labial bone defect when immediate implant of anterior maxillary., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Xianli Wang et al.)

Three-dimensional aggregate-suspension culture is a potential biomanufacturing method to produce a large number of human induced pluripotent stem cells (hiPSCs); however, the use of expensive growth factors and method-induced mechanical stress potentially result in inefficient production costs and difficulties in preserving pluripotency, respectively. Here, we developed a simple, miniaturized, dual-compartment dialysis-culture device based on a conventional membrane-culture insert with deep well plates. The device improved cell expansion up to approximately ~3.2 to 4×10 7 cells/mL. The high-density expansion was supported by reduction of excessive shear stress and agglomeration mediated by the addition of the functional polymer FP003. The results revealed accumulation of several growth factors, including fibroblast growth factor 2 and insulin, along with endogenous Nodal, which acts as a substitute for depleted transforming growth factor-β1 in maintaining pluripotency. Because we used the same growth-factor formulation per volume in the upper culture compartment, the cost reduced in inverse proportional manner with the cell density. We showed that growth-factor-accumulation dynamics in a low-shear-stress environment successfully improved hiPSC proliferation, pluripotency, and differentiation potential. This miniaturised dialysis-culture system demonstrated the feasibility of cost-effective mass production of hiPSCs in high-density culture., (© 2021. The Author(s).)

Significance: Wound healing involves the phasic production of growth factors (GFs) and cytokines to progress an acute wound to a resolved scar. Dysregulation of these proteins contributes to both wound chronicity and excessive scarring. Direct supplementation of GFs and cytokines for treatment of healing and scarring complications has, however, been disappointing. Failings likely relate to an inability to deliver recombinant proteins at physiologically relevant levels to an environment conducive to healing. Recent Advances: Inspired by the extracellular matrix, natural biomaterials have been developed that resemble human skin, and are capable of delivering bioactives. Hybrid biomaterials made using multiple polymers, fabrication methods, and proteins are proving efficacious in animal models of acute and impaired wound healing. Critical Issues: For clinical translation, these delivery systems must be tailored for specific wound indications and the correct phase of healing. GFs and cytokines must be delivered in a controlled manner that will target specific healing or scarring impairments. Preclinical assessment in clinically relevant animal models of impaired or excessive healing is critical. Future Directions: Clinical success will likely depend on the GF or cytokine selected, their compatibility with the chosen biomaterial(s), degradation rate of the fabricated system, and the degree of control over release kinetics. Further testing is essential to assess which wound indications are most suited to specific delivery systems and to prove whether they provide superior efficacy over direct protein therapies.

Autoreactive T cell is one of the leading causes of immunological tolerance defects in the chronic inflammatory lesions of rheumatoid arthritis (RA). There have been several extracellular signals and intracellular pathways reported in regulating this process but largely remain unknown yet. In this study, we explored the roles of intestinal Wnt/β-catenin on disease severity during collagen-induced arthritis model (CIA), an animal model of RA. We first testified the activity pattern Wnt/β-catenin shifted by intragastric administration of LiCl and DKK-1 in the intestine by real-time PCR and WB analysis. The arthritis scores showing the disease severity in the DKK-1 group was significantly ameliorated compared with the control group at the late stage of the disease, while in the LiCl group, the scores were significantly elevated which was consistent with pathology score analysis of H&E staining. Next, ELISA was performed and showed that TNF-α and IL-17 in the LiCl group were significantly higher than that of the control group. IL-10 in the DKK-1 group was significantly higher than that in the LiCl-1 group and control group, P < 0.05. Flow cytometry of spleen T cells differentiation ratio showed that: Th1 from the DKK-1 and LiCl groups and Th17 from the LiCl group was significantly different from that of the blank model group, P < 0.05. Finally, we explored the effects of intestinal Wnt/β-catenin on T cell differentiation regulator ROR-γt and TCF1 and found that both transcription factors were up-regulated in the LiCl group. Together, these data suggested the pro-information role of Wnt/β-catenin pathway from the intestine in the CIA mouse, implying its use as a potential therapeutic target for the treatment of inflammatory diseases such as RA., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Nocturia is a major problem in geriatric patients. Clock genes regulate circadian bladder function and Piezo type mechanosensitive ion channel component 1 (Piezo1) that senses bladder fullness. We utilized WT and Clock mutant (Clock Δ19/Δ19 : nocturia phenotype) mice to determine if the effects of GsMTx4, a Piezo1 inhibitor, is dependent on circadian Piezo1 expression in the bladder., Methods: We compared voiding behavior in mice after the administration of vehicle, low dose, or high dose of GsMTx4. Intraperitoneal injections (IP) were performed at Zeitgeber time (ZT) 0, lower Piezo1 expression phase (ZT0-IP) and ZT12, higher Piezo1 expression phase (ZT12-IP). Urine volume (Uvol), voiding frequency (VF), and urine volume per void (Uvol/v) were measured using metabolic cages., Results: VF decreased at ZT12-IP in WT mice only with high dose of GsMTx4 but showed no effects in Clock Δ19/Δ19 mice. VF decreased significantly at ZT0-IP in WT mice after both doses, but only decreased after high dose in Clock Δ19/Δ19 mice. Uvol/v increased in WT mice at ZT0-IP after both doses and at ZT12-IP after high dose. Uvol/v increased in Clock Δ19/Δ19 mice only at ZT0-IP after high dose. GsMTx4 did not affect Uvol in both mice at ZT12-IP. A decrease in Uvol was observed in both mice at ZT0-IP; however, it was unrelated to GsMTx4-IP., Conclusions: The effects of GsMTx4 changed associated with the circadian clock and Piezo1 expression level. The maximum effect occurred during sleep phase in WT. These results may lead to new therapeutic strategies against nocturia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Growth factors (GFs) are indispensable in regenerative medicine because of their high effectiveness. However, as GFs degenerate easily, the development of a suitable carrier with improved stability for GFs is necessary. In this study, we developed a gel-in-oil (G/O) emulsion technology for the transdermal delivery of growth factors. Nanogel particles prepared with heparin-immobilized gelatin that can bind growth factors were dispersed in isopropyl myristate. The particle size of the G/O emulsion could be controlled by changing the surfactant concentration, volume ratio of the water phase to the oil phase, and gelatin concentration. In vitro skin penetration studies showed better penetration through the stratum corneum of fluorescent proteins containing G/O emulsions than of the aqueous solution of GF. Similarly, an in vivo study showed an angiogenesis-inducing effect after transdermal application of GF-immobilized G/O emulsion. Angiogenesis in mice was confirmed owing to both an increased blood vessel network and higher hemoglobin content in the blood. Therefore, the G/O emulsion could be a promising carrier for GFs with better stability and can effectively deliver GFs at the target site., (Copyright © 2021 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

It has been established that cisplatin causes neuronal damage and cognitive impairment. However, the mechanism is not sufficiently clear. Apelin-13 is an endogenous peptide with strong neuroprotective effects through the synthesis of neurotrophic factors and suppression of inflammation. The aim of this study was to investigate the role of brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway and the potential inhibitory effects of apelin-13 in the mechanism of cisplatin-induced hippocampal damage and cognitive impairment. Apelin-13 was administered to adult sprague dawley male rats at a dose of 20 nmol/kg every day for 4 weeks, cisplatin was administered at a dose of 5 mg/kg once a week for 4 weeks. The spatial and recognition memory tests of the rats were performed on the 5th week. BDNF and the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels were measured by ELISA in hippocampal homogenates. Pyramidal neuron and glial cell damage in the hippocampal CA1, CA3 and dentate gyrus (DG) were analyzed histologically. TrkB activity in the hippocampus was determined by immunohistochemical methods. Cisplatin impaired spatial and recognition memory in rats, while apelin-13 improved spatial memory but did not affect recognition memory. Cisplatin suppressed BDNF in the hippocampus while increased IL-1β and TNF-α. In contrast, apelin-13 administration increased BDNF but significantly suppressed TNF-α and IL-1B. Cisplatin caused pyramidal neuron and glial cell damage in CA1, CA3 and DG. In the cisplatin + apelin-13 group, however, pyramidal neuron and glial cell damage was less than those without apelin-13. Cisplatin increased TrkB activity in the hippocampus, which was counteracted by apelin-13. In conclusion, apelin-13 reduced the cisplatin-induced cognitive deficiency, by suppressing inflammation and stimulating the synthesis and activation of neurotrophic factors in hippocampal tissue., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Endometrial receptivity and thickness play an important role in achieving a pregnancy. Intrauterine autologous platelet-rich plasma (PRP) infusion has been used in infertile women with recurrent implantation failure (RIF) and thin endometrial lining thickness (EMT). Literature search was performed in PubMed for studies including in vitro, animal, and human studies as well as in abstracts presented at national conferences. Animal studies demonstrated a decrease in the expression of inflammatory markers and fibrosis, and increased endometrial proliferation rate, increased expression of proliferative genes, and increased pregnancy rates. The in vitro studies showed that PRP was associated with increased stromal and mesenchymal cell proliferation, increased expression of regenerative enzymes, and enhancement in cell migration. In infertile women undergoing assisted reproductive technology, one randomized clinical trial showed that PRP intrauterine infusion improved EMT, implantation rate, and clinical pregnancy rate (CPR) in patients with thin EMT, while 3 other trials involving subjects with RIF showed conflicting results related to CPR. Case series and cohort studies showed conflicting results pertaining to CPR. Data to date suggest that PRP may be beneficial in improving endometrial thickness and endometrial receptivity. However, further large prospective and high-quality trials are needed to assert its effect and to identify the population of patients that would benefit the most.

Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually used when the non-operative treatment is not effective, and when the surgery is not yet indicated. More and more studies suggesting that IA injections are as or even more efficient and safe than NSAIDs. Recently, research to improve intra-articular homeostasis has focused on biologic adjuncts, such as platelet-rich plasma (PRP). The catabolic and inflammatory intra-articular processes that exists in knee osteoarthritis (KOA) may be influenced by the administration of PRP and its derivatives. PRP can induce a regenerative response and lead to the improvement of metabolic functions of damaged structures. However, the positive effect on chondrogenesis and proliferation of mesenchymal stem cells (MSC) is still highly controversial. Recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, significant progress has been made in understanding the mechanism of PRP action. In this review, we will discuss mechanisms related to inflammation and chondrogenesis in cartilage repair and regenerative processes after PRP administration in in vitro and animal studies. Furthermore, we review clinical trials of PRP efficiency in changing the OA biomarkers in knee joint.

Acid bone lysates (ABLs) represent the growth factors and other molecules released during autologous graft resorption. However, the impact of these bone-derived growth factors on the healing of bone defects has not yet been investigated. The aim of the present study was, therefore, to examine the impact of ABLs adsorbed to collagen membranes on bone regeneration. To this end, in 16 female Sprague Dawley rats, a standardized 5-mm-diameter critical size defect on the calvarial bone was created. The defects were covered with collagen membranes that had been soaked either in serum-free media or ABLs followed by lyophilization. After a healing period of 4 weeks, micro-computed tomography (μCT) and histological analyses by means of undecalcified thin ground sections were performed. μCT analysis of the inner 4 mm of the calvaria defect showed a greater bone defect coverage in the control group when compared to ABL group, 29.8% (confidence interval [CI]: 17.7-50.3) versus 5.6% (CI: 1.0-29.8, p = .03), respectively. Moreover, we found significantly more absolute bone volume (BV) in the control group when compared to ABL group, 0.59 mm 3 (CI: 0.27-1.25) versus 0.07 mm 3 (CI: 0.06-0.59, p = .04), respectively. Histomorphometry confirmed these findings with a relative BV in the central compartment of 14.1% (CI: 8.4-20.6) versus 5.6% (CI: 3.4-7.9, p = .004), respectively. These findings indicate that bone-derived growth factors contained in ABLs are able to attenuate bone regeneration within collagen membranes., (© 2020 The Authors. Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

Spinal cord injury (SCI) can cause various symptoms, including pain, complete or incomplete loss of autonomic, sensory, motor and functions inferior to the site of the damage. Despite wondrous advances in medicine, treating spinal cord injuries remains a thorny issue yet. Recently, the control of inflammatory processes after damage to the nervous system has been noticed as a promising therapeutic target. The goal of the present experiment was to identify the effects of apelin-13 on the histological outcome, inflammatory factors, and functional recovery in the animal contusion model of SCI were analyzed. 40 Female Wistar rats were randomly but equally assigned in laminectomy, contusion, PBS (1 mL PBS, i.p), control group which received apelin-13 (control + apelin, 100 μg/kg, i.p), and apelin-13 treatment groups. In the treatment group, apelin-13 (100 μg/kg) was injected intraperitoneally 30 min after injury. The weight-dropping contusion model was used for inducing SCI. The Basso, Beattie, and Bresnahan scale (BBB), narrow beam test (NBT), rotarod test, and the open-field test was applied to evaluate locomotor and behavioral activity. Real-time polymerase chain reaction (PCR) and ELISA technique was accomplished eight weeks after inducing SCI to measure the level of fibroblast growth factor FGF-1, FGFR1 and the inflammatory factors including interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-6, and IL-10. Furthermore, histological change was estimated by H&E staining. Our results showed that apelin-13 treatment after SCI led to a significant increase in functional recovery and behavioral tests. Stereological estimation illustrated that apelin-13 could reduce significantly central cavity volume and number of glial cells, and also increase significantly spinal cord volume and number of neural cells. PCR and ELISA evaluation shows a significant increase in IL-10 level and decrease in levels of FGF-1, FGF-R1, and pro-inflammatory cytokines (PIC). This study suggested that apelin-13 has neuroprotective effects by regulating the inflammatory process after SCI., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sepsis is a widespread life-threatening disease, with a high mortality rate due to inflammation-induced multiorgan failure (MOF). Thus, new effective modulators of the immune response are urgently needed to ameliorate the outcome of septic patients. As growth arrest-specific gene 6 (Gas6)/Tyro3, Axl, MerTK (TAM) receptors signaling has shown immunomodulatory activity in sepsis, here we sought to determine whether Gas6 protein injection could mitigate MOF in a cecal slurry mouse model of sepsis. Mice, divided into different groups according to treatment-i.e., placebo (B), ampicillin (BA), Gas6 alone (BG), and ampicillin plus Gas6 (BAG)-were assessed for vitality, histopathology and cytokine expression profile as well as inducible nitric oxide synthase (iNOS), ALT and LDH levels. BAG-treated mice displayed milder kidney and lung damage and reduced levels of cytokine expression and iNOS in the lungs compared to BA-treated mice. Notably, BAG-treated mice showed lower LDH levels compared to controls. Lastly, BAG-treated cells of dendritic, endothelial or monocytic origin displayed reduced ROS formation and increased cell viability, with a marked upregulation of mitochondrial activity. Altogether, our findings indicate that combined treatment with Gas6 and antibiotics ameliorates sepsis-induced organ damage and reduces systemic LDH levels in mice, suggesting that Gas6 intravenous injection may be a viable therapeutic option in sepsis.

The sophisticated chain of cellular and molecular episodes during wound healing includes cell migration, cell proliferation, deposition of extracellular matrix, and remodelling and are onerous to replicate. Encapsulation of growth factors (GFs) and Stem cell-based (SCs) has been proclaimed to accelerate healing by transforming every phase associated with wound healing to enhance skin regeneration. Therapeutic application of mesenchymal stem cells (MSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (PSCs) provides aid in wound fixing, tissue integrity restoration and function of impaired tissue. Several scientific studies have established the essential role GFs in wound healing and their reduced degree in the chronic wound. The overall limitation includes half-life, unfriendly microhabitat abundant with protease, and inadequate delivery approaches results in decreased delivery of effective amounts in a suitable time-based fashion. Advancements in the area of reformative medicine as well as tissue engineering have offered techniques competent of dispensing SCs and GFs in site-oriented manner. The progress in nanotechnology-based approaches attracts researcher to study and evaluate the potential of this SCs and GFs based therapy in chronic wounds. These techniques embrace the polymeric regime viz., nano-formulations, hydrogels, liposomes, scaffolds, nanofibers, metallic nanoparticles, lipid-based nanoparticles and dendrimers that have established better retort through targeting tissues when GFs and SCs are transported via these humans made devices. Assumed the current problems, improvements in delivery approaches and difficulties offered by chronic wounds, we hope to show that encapsulation of SCs and GFs loaded nanoformulations therapies is the rational next step in improving wound care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Gremlin 1 (GREM1) is a secreted BMP2/4 inhibitor which regulates commitment and differentiation of human adipose precursor cells and prevents the browning effect of BMP4. GREM1 is an insulin antagonist and serum levels are high in type 2 diabetes (T2D). We here examined in vivo effects of AAV8 (Adeno-Associated Viral vectors of serotype eight) GREM 1 targeting the liver in mature mice to increase its systemic secretion and also, in a separate study, injected recombinant GREM 1 intraperitoneally. The objective was to characterize systemic effects of GREM 1 on insulin sensitivity, glucose tolerance, body weight, adipose cell browning and other local tissue effects., Methods: Adult mice were injected with AAV8 vectors expressing GREM1 in the liver or receiving regular intra-peritoneal injections of recombinant GREM1 protein. The mice were fed with a low fat or high fat diet (HFD) and followed over time., Results: Liver-targeted AAV8-GREM1 did not alter body weight, whole-body glucose and insulin tolerance, or adipose tissue gene expression. Although GREM1 protein accumulated in liver cells, GREM1 serum levels were not increased suggesting that it may not have been normally processed for secretion. Hepatic lipid accumulation, inflammation and fibrosis were also not changed. Repeated intraperitoneal rec-GREM1 injections for 5 weeks were also without effects on body weight and insulin sensitivity. UCP1 was slightly but significantly reduced in both white and brown adipose tissue but this was not of sufficient magnitude to alter body weight. We validated that recombinant GREM1 inhibited BMP4-induced pSMAD1/5/9 in murine cells in vitro, but saw no direct inhibitory effect on insulin signalling and pAkt (ser 473 and thr 308) activation., Conclusion: GREM1 accumulates intracellularly when overexpressed in the liver cells of mature mice and is apparently not normally processed/secreted. However, also repeated intraperitoneal injections were without effects on body weight and insulin sensitivity and adipose tissue UCP1 levels were only marginally reduced. These results suggest that mature mice do not readily respond to GREMLIN 1 but treatment of murine cells with GREMLIN 1 protein in vitro validated its inhibitory effect on BMP4 signalling while insulin signalling was not altered., Competing Interests: All authors declare that they have no competing interests and that the funding of SH, CC and JB by Astra Zeneca only relates to funding these salaries. Furthermore, this funding does not alter our adherence to PLOS ONE policies on sharing data and materials.

One of the most severe effects of coronavirus disease 2019 (COVID-19) is lung disorders such as acute respiratory distress syndrome. In the absence of effective treatments, it is necessary to search for new therapies and therapeutic targets. Platelets play a fundamental role in respiratory disorders resulting from viral infections, being the first line of defense against viruses and essential in maintaining lung function. The direct application of platelet lysate (PL) obtained from the platelet-rich plasma of healthy donors could help in the improvement of the patient due its anti-inflammatory, immunomodulatory, antifibrotic, and repairing effects. This work evaluates PL nebulization by analyzing its levels of growth factors and its biological activity on lung fibroblast cell cultures, besides describing a scientific basis for its use in this kind of pathology. The data of the work suggest that the molecular levels and biological activity of the PL are maintained after nebulization. Airway administration would allow acting directly on the lung tissue modulating inflammation and stimulating reparative processes on key structures such as the alveolocapillary barrier, improving the disease and sequels. The protocol developed in this work is a first step for the study of nebulized PL both in animal experimentation and in clinical trials.

Abstract: To evaluate the efficacy and safety of plasma rich in growth factors (PRGF) in photorefractive keratectomy (PRK) versus Mitomycin C (MMC).This is a comparative, longitudinal and retrospective case-control study (MMC vs PRGF), in patients with a spherical correction from -0.25 to -8.00 D and cylinder correction from -0.25 to -3.00. The uncorrected distance visual acuity (UDVA), refractive efficacy and safety indices, and changes in endothelial cell density were evaluated. The predictability was assessed with the postoperative manifest spherical equivalent.Forty-four patients (72 eyes) were treated with MMC and twenty-five patients (45 eyes) with PRGF. The final UDVA (LogMar) in MMC was 0.029 ± 0.065 and in PRGF it was 0.028 ± 0.048 (p = 0.383). The efficacy index for MMC was 0.98 ± 0.10 and 1.10 ± 0.46 for patients treated with PRGF (p = 0.062). The safety index for MMC was 1.03 ± 0.11 and 1.12 ± 0.46 (p = 0.158) for PRGF group. The change percentage of endothelial cell density was 0.9 ± 11.6 for MMC and 4.3 ± 13.1 for PRGF (p = 0.593). The predictability for MMC was 92.1% and for the PRGF was 91.9% (p = 0.976). Hyperemia, eye pain and superficial keratitis were observed in 11.1% of the MMC group; no adverse events were observed with the PRGF.The use of PRGF in PRK surgery is as effective as MMC. The PRGF shows a better safety profile than MMC for its intraoperative use in PRK., Competing Interests: The authors declare the following competing financial interest(s): E.A. is the Scientific Director of BTI Biotechnology Institute, R.M.S.A and F.M are scientists at BTI Biotechnology Institute, a dental implant company, that investigates in the fields of oral implantology and PRGF-Endoret technology. The rest of the authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Oxidative damage to cells from metabolites at a wound site is one of the trickiest factors inhibiting tissue regeneration, especially with bulk damage. In addition, an excessive inflammatory reaction by the body at the wound site can make it even worse. How to scavenge the reactive oxygen species (ROS) produced from metabolism and inflammatory reactions has become a critical issue in tissue engineering. Here, we utilize the natural bioactive small molecules l-arginine and l-phenylalanine and the growth factor inositol to synthesize a branched poly(ester amide) (BPEA) to fabricate BPEA nanocapsules for vitamin E delivery at wound sites. BPEA nanocapsules loaded with vitamin E (BPEA@VE NCs) could protect cells from both extracellular and intracellular damage by scavenging ROS. Simultaneously, the inflammatory reaction could also be downregulated, benefiting from the introduction of l-arginine. Furthermore, the biodegradation products of BPEA are natural metabolites of the body, such as amino acids and growth factors, guaranteeing the biocompatibility of the BPEA@VE NCs. The protective ability of the BPEA@VE NCs was also investigated in vivo for accelerated wound healing. All the results indicate that the BPEA@VE NCs have promising potential for the modulation of the local microenvironment in tissue engineering for excellent antioxidative and anti-inflammatory properties.

Introduction: Inspired by application of platelet-rich plasma (PRP) in skin treatment during injuries, an extracting method was developed here to recover high amounts of cytokines and growth factors from PRP; this prepared extract was named as self-growth colony (SGC)., Methods: In optimization of SGC preparation, various parameters were tested, for example, centrifugation force, freeze-thaw, sonication, and inclusion of calcium chelator. The amounts of cytokines and growth factors, including platelet factor 4, β-thromboglobulin, epidermal growth factor, vascular endothelial growth factor, platelet-derived growth factor, were measured by ELISA assay., Results: By comparing to PRP, the prepared SGC contained a significant higher amount of measured growth factors. In addition, the degradation of growth factors within SGC during the storage was calibrated, which showed better stability as compared to that of PRP preparation. Having possible application in skin care, the optimized SGC was chemically standardized by using the enrichment of growth factors. Application of SGC in cultured keratinocytes stimulated the wound healing of injured cultures. In line to this notion, SGC was applied onto human skin, and thereafter the robust improvement of skin properties was revealed., Conclusions: The potential application of SGC in treating skin rejuvenation and ageing, as well as its elaborated application for medical purpose, that is, wound healing, was illustrated., (© 2021 S. Karger AG, Basel.)

The antidepressant effect of eicosapentaenoic acid-derived bioactive lipid, resolvin E1 (RvE1), was examined in a murine model of chronic pain-induced depression using a tail suspension test. Because RvE1 reportedly possesses agonistic activity on a chemerin receptor ChemR23, we also examined the antidepressant effect of chemerin. Two weeks after surgery for unilateral spared nerve injury to prepare neuropathic pain model mice, immobility time was measured in a tail suspension test. Chronic pain significantly increased immobility time, and this depression-like behavior was attenuated by intracerebroventricular injection of RvE1 (1 ng) or chemerin (500 ng). These results demonstrate that RvE1 exerts an antidepressant effect in a murine model of chronic pain-induced depression, which is likely to be via ChemR23. RvE1 and its receptor may be promising targets to develop novel antidepressants.

Bone tissue engineering strategies have been developed to address the limitations of the current gold standard treatment options for bone-related disorders. These systems consist of an engineered scaffold that mimics the extracellular matrix and provides an architecture to guide the natural bone regeneration process, and incorporated growth factors that enhance cell recruitment and ingress into the scaffold and promote the osteogenic differentiation of stem cells and angiogenesis. In particular, the osteogenic growth factor bone morphogenetic protein 2 (BMP-2) has been widely studied as a potent agent to improve bone regeneration. A key challenge in growth factor delivery is that the growth factors must reach their target sites without losing bioactivity and remain in the location for an extended period to effectively aid in the formation of new bone. Protein incorporation into nanoparticles can both protect protein bioactivity and enable its sustained release. In this study, a poly(methyl methacrylate-co-methacrylic acid) nanoparticle-based system was synthesized incorporating a custom poly(ethylene glycol) dimethacrylate crosslinker. It was demonstrated that the nanoparticle degradation rate can be controlled by tuning the number of hydrolytically degradable ester units along the crosslinker. We also showed that the nanoparticles had high affinity for a model protein for BMP-2, and optimal conditions for maximum protein loading efficiency were elucidated. Ultimately, the proposed system and its high degree of tunability can be applied to a wide range of growth factors and tissue engineering applications. Impact Statement In this study, we developed a novel method of synthesizing nanoparticles with tunable degradation rates through the incorporation of a custom synthesized, hydrolytically degradable crosslinker. In addition, we demonstrated the affinity of the synthesized nanoparticles for a model protein for bone morphogenetic protein 2 (BMP-2). The tunability of these nanoparticles can be used to develop complex tissue engineering systems, for example, for the delivery of multiple growth factors involved at different stages of the bone regeneration process.

Growth factors are multi-functional signaling molecules that coordinate multi-stage process of wound healing. During wound healing, growth factors are transmitted to wound environment in a positive and physiologically related way, therefore, there is a broad prospect for studying the mediated healing process through growth factors. However, growth factors (GFs) themselves have disadvantages of instability, short life, rapid inactivation of physiological conditions, low safety and easy degradation, which hinder the clinical use of GFs. Rapid development of delivery strategies for GFs has been trying to solve the instability and insecurity of GFs. Particularly, in recent years, GFs delivered by scaffolds based on biomaterials have become a hotspot in this filed. This review introduces various delivery strategies for growth factors based on new biodegradable materials, especially polysaccharides, which could provide guidance for the development of the delivery strategies for growth factors in clinic.

Cholangiocarcinoma (CCA) has a poor prognosis and high chemoresistance. Interleukin-4 receptor (IL-4R) is overexpressed in several cancer cells and plays a crucial role in tumor progression and drug resistance. IL4RPep-1, an IL-4R-binding peptide, has been identified by phage display and used for tumor targeting. In this study, we exploited IL4RPep-1 to guide the tumor-specific delivery of a proapoptotic peptide to chemoresistant CCA, thereby inhibiting tumor growth. Immunohistochemistry of human primary CCA tissues showed that IL-4R levels were upregulated in moderately to poorly differentiated types, and higher levels of IL-4R are correlated with lower survival rates in patients with CCA. IL4RPep-1 was observed to preferentially bind with high IL-4R-expressing KKU-213 human CCA cells, whereas it barely bound with low IL-4R-expressing KKU-055 cells. A hybrid of IL4RPep-1 and a proapoptotic peptide (KLAKLAK)2 (named as IL4RPep-1-KLA) induced cytotoxicity and apoptosis in KKU-213 cells and increased those levels induced by 5-fluorouracil (5-FU). IL4RPep-1-KLA was internalized in the cells and colocalized with mitochondria. Whole-body fluorescence imaging and immunohistochemical analysis of tumor tissues showed the homing of IL4RPep-1-KLA as well as IL4RPep-1 to KKU-213 tumor in mice. Systemic administration of IL4RPep-1-KLA efficiently inhibited KKU-213 tumor growth, whereas treatment with 5-FU alone did not significantly inhibit tumor growth in mice. No significant systemic side effects including liver toxicity and immunotoxicity were observed in mice during peptide treatments. These findings suggest that IL4RPep-1-KLA holds potential as a targeted therapeutic agent against chemoresistant CCA.

Background: The aim of this study was to evaluate the efficacy and safety of injection of allogeneic growth factors in patients with plantar fasciitis., Methods: This study included 150 patients who were randomly divided into 2 equal groups; the patients were locally injected with allogeneic growth factors (GFs) (treatment group) or with saline 0.9% (control group). The patients were assessed using visual analog scale (VAS) and Foot Function Index-Revised short form (FFI-Rs) scores preinjection and 1, 3, 6, and 12 months postinjection. The patients were questioned about their satisfaction. Any adverse effects were recorded., Results: At baseline, there was no significant difference between both groups regarding the mean VAS and FFI-Rs scores. At 3-month follow-up, the reduction in mean VAS score was 87% in the treatment group and 55% in the control group ( P < .001), and the reduction in mean FFI-Rs score was 62% in the treatment group and 40% in the control group ( P < .001). Treatment group and study visit were significant factors affecting both VAS and FFI-Rs scores. Overall, 92% were satisfied in the treatment group, and 78.2% in the control group. Postinjection pain occurred in 5 patients in the treatment group., Conclusion: This study provides Level I evidence regarding the efficacy and safety of allogeneic GF injection in patients with plantar fasciitis. However, additional studies are needed to evaluate their adverse effects, immunogenicity, and microbiological safety., Level of Evidence: Level I, prospective randomized controlled case series.

Objective: Chronic wounds are long-term nonhealing wounds that are refractory to treatment. These wounds can present elevated protease levels, leading to rapid degradation of native and exogenously added growth factors. This work focused on developing a protease-resistant growth factor formulation for treatment of chronic wounds presented with high protease activity. Approach: This study developed protease-resistant growth factor formulations comprising elastin-like peptides (ELPs) fused with a known protease inhibitor peptide or growth factor. The ELP component of the fusion proteins allows assembly of heterogeneous nanoparticles (NPs) putting the inhibitor in close proximity to the growth factor to be protected. Results: We show successful preservation of growth factor activity in high human neutrophil elastase (HNE) environment and in human chronic wound fluid derived from patients. We further show that these NPs result in enhanced collagen remodeling and resolution of inflammation in a full thickness wound supplemented with HNE in genetically diabetic mice. Innovation: Development of heterogeneous NPs that put the protease inhibitor in close proximity of the growth factor. Moreover, the modular nature of the NPs allows for protection of multiple growth factors by the same inhibitor without changing the amino acid sequence of the growth factor. Conclusion: Our results indicate that the developed NPs hold tremendous promise in chronic wound healing therapy and may further help the translation of growth factor therapies to clinic. The customizable template for the NP design allows for multifaceted use across several fields in research and medicine.

A nonplanar polylactide scaffold to be used in tissue engineering was obtained by freeze-extraction method. Properties of the scaffold were modified by adding Eudragit® E100. The impact of the modification on morphology, porosity and pore size, mass absorbability, mechanical properties was determined. Scanning electron microscopy (SEM), hydrostatic weighing test, static compression test was used to this end. The chemical composition of the scaffold was defined based on infrared spectroscopy (FTIR) and energy-dispersive X-ray spectroscopy (EDX). Biocompatibility was confirmed by quantitative tests and microscopic observation. The obtained results show that the obtained scaffolds may be applied as a carrier of hydrophilic cellular growth factors for more efficient tissue regeneration., (© 2020 Wiley Periodicals, Inc.)

Laser resurfacing has progressed since the 1980s to treat a variety of medical and aesthetic indications with ever-evolving safety parameters. While laser technology has evolved to provide a more favorable safety profile and decrease wound healing time, advances in post-procedure healing agents have also helped to mitigate adverse effects, such as persistent erythema, dyspigmentation, acneiform eruptions, dermatitis, infections, and scarring. We reviewed the evidence of growth factors, stem cells, silicone and silicone polymers, botanical based treatments, fatty acids, probiotics, and closed dressings on post-ablative laser skin resurfacing. All reviewed agents demonstrated some evidence in improving post-procedure outcomes, albeit mixed in many cases. Additionally, these studies contain small numbers of participants, vary in type, strength, and clinical indication for which the resurfacing laser was used, and have differing postprocedural evaluation protocols and assessments. This highlights a need for standardization of clinical studies and the importance of choosing an optimal postprocedural skincare plan depending on every unique clinical scenario. J Drugs Dermatol. 2020;19(11):1050-1055. doi:10.36849/JDD.2020.5386.

Introduction: Infected chronic wounds particularly diabetic foot ulcers (DFUs) can result from stable colonization of antibiotic-resistant bacteria and fungi at the wound sites. In this context, the rapid healing of infected wounds has been the main goal in recent investigations. This issue can be solved by improving wound-healing phases including hemostasis, inflammatory, proliferative, and remodeling/maturation, and removal of bacteria and fungi. The applications of growth factors (GFs) and metal/metal oxide nanoparticles (MNPs/MONPs) are two choices for these targets. However, the lack of sustainable release of these agents is an important problem for appropriate wound healing., Area Covered: The present review is focused on recent advances in delivery systems composed of growth factor and MNPs/MONPs for rapid wound healing., Expert Opinion: Synthetic and natural polymeric micro- and nanocarriers including polyvinylpyrrolidone (PVP) and chitosan play a vital role in the healing of infected chronic wounds. Using various derivatives of chitosan as pH-responsive polymer with basic and acidic groups can be the best option to prepare controllable and sequential GF release. However, it warrants further extensive research to solve wound-healing problems.

Pyloric metaplasia (PM) and pseudopyloric metaplasia (PPM) are metaplastic changes resulting in pyloric-type glands in the gastric oxyntic mucosa that mainly occur in chronic gastritis caused by Helicobacter pylori (H. pylori) infection. Focusing on PM and PPM, we classified the histological changes in gastric mucosa according to the Updated Sydney System, using 314 biopsy specimens of gastric greater curvature of the middle body before H. pylori eradication (HPE). Next, the numbers of PM and PPM glands were counted in 47 specimens, and subjects were followed up over 10 years after HPE. PPM was recognized jointly with inflammation, activity, atrophy, and intestinal metaplasia, but PM was recognized more frequently than PPM as atrophy and intestinal metaplasia progressed. Both PM and PPM regressed significantly within 6 years after HPE. Additionally, we demonstrated that PM and PPM are not always coincident with spasmolytic polypeptide-expressing metaplasia (SPEM). In conclusion, PM and PPM are considered different modulations of the same line of differentiation, which are both reversible, with PM potentially emerging from PPM upon progression.

This study evaluated the effect of thermosensitive hydroxybutyl chitosan (HBC) hydrogel loaded with human platelet lysate (hPL) on skin wound healing in rats. hPLs were generated by freeze-thaw method of platelet-rich plasma from healthy donors. Successful grafting of hydroxybutyl group to chitosan molecular chain to obtain HBC hydrogel was confirmed by Fourier-transform infrared spectroscopy. HBC/hPL was prepared by combining 10% (vol/vol) hPL with HBC solution. Surface morphologies were determined by Scanning Electron Microscopy, rheological properties were measured by rheometer, and sustained release of factors from HBC/hPL was measured by enzyme-linked immunoassay. We evaluated the in vitro effect of HBC/hPL on human umbilical cord vein endothelial cell (HUVEC) proliferation, migration, and tube formation. The effect of growth factors released from HBC/hPL in promoting skin wound healing was evaluated by gross observation, histology, immunohistochemistry, and immunofluorescence in vivo. Rheological analyses indicated the gelation temperatures of HBC and HBC/hPL were 17 and 14°C, respectively. ELISA showed sustained release of human platelet-derived growth factor, basic fibroblast growth factor, and transforming growth factor-β1 from HBC/hPL hydrogel. In vitro studies revealed HBC/hPL promoted greater levels of HUVECs proliferation, migration, and tube formation than the HBC and control groups. In vivo studies showed better wound healing, greater amounts of newly formed collagen, as well as neovascular and neo-epidermis markers in the wound site of HBC/hPL-treated group compared to the HBC and control groups. HBC/hPL is a promising potential therapeutic agent for promoting skin wound healing via the sustained release of growth factors., (© 2020 Wiley Periodicals, Inc.)

Background: Modern surgeries have advanced toward personalized minimal-invasive treatments with a high rate of clinical healing that facilitates the regeneration of tissues. One of the leading approaches to deliver endogenous plasma- and platelet-derived growth factors is the plasma rich in growth factors (PRGF). This narrative review determines the effects of using PRGF in different oral surgical procedures including alveolar ridge augmentation, socket preservation, sinus floor augmentation and periodontal regeneration., Methods: For this narrative review, a literature search was conducted using PubMed and Researchgate. A combination of the following text words was used to maximize search specificity and sensitivity: "platelet-rich plasma", "PRP", "PRGF", "Platelet-rich growth factor", "socket preservation", "Extraction", "infra-bony pockets", "sinus floor augmentation", "randomized clinical controlled trials", "Alveolar osteitis", "Periodontal regeneration", "guided bone regeneration", "guided tissue regeneration"., Results: Investigations have generally agreed that PRGF can promote and accelerate the healing process. PRGF optimizes the patient's quality of life by reducing pain, swelling and inflammation rate and also accelerates regeneration of soft tissue and bone tissue regeneration as well., Conclusions: There is increasing evidence to support the use of PRGF in oral surgical procedures in order to improve the healing processes of the oral soft and hard tissues., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Myocardial infarction causes cardiac tissue damage and the release of damage-associated molecular patterns leads to activation of the immune system, production of inflammatory mediators, and migration of various cells to the site of infarction. This complex response further aggravates tissue damage by generating oxidative stress, but it eventually heals the infarction site with the formation of fibrotic tissue and left ventricle remodeling. However, the limited self-renewal capability of cardiomyocytes cannot support sufficient cardiac tissue regeneration after extensive myocardial injury, thus, leading to an irreversible decline in heart function. Approaches to improve cardiac tissue regeneration include transplantation of stem cells and delivery of inflammation modulatory and wound healing factors. Nevertheless, the harsh environment at the site of infarction, which consists of, but is not limited to, oxidative stress, hypoxia, and deficiency of nutrients, is detrimental to stem cell survival and the bioactivity of the delivered factors. The use of biomaterials represents a unique and innovative approach for protecting the loaded factors from degradation, decreasing side effects by reducing the used dosage, and increasing the retention and survival rate of the loaded cells. Biomaterials with loaded stem cells and immunomodulating and tissue-regenerating factors can be used to ameliorate inflammation, improve angiogenesis, reduce fibrosis, and generate functional cardiac tissue. In this review, we discuss recent findings in the utilization of biomaterials to enhance cytokine/growth factor and stem cell therapy for cardiac tissue regeneration in small animals with myocardial infarction.

The development of biomaterials, stem cells and bioactive factors has led to cartilage tissue engineering becoming a promising tactic to repair cartilage defects. Various polymer three-dimensional scaffolds that provide an extracellular matrix (ECM) mimicking environment play an important role in promoting cartilage regeneration. In addition, numerous growth factors have been found in the regenerative process. However, it has been elucidated that the uncontrolled delivery of these factors cannot fully exert regenerative potential and can also elicit undesired side effects. Considering the complexity of the ECM, neither scaffolds nor growth factors can independently obtain successful outcomes in cartilage tissue engineering. Therefore, collectively, an appropriate combination of growth factors and scaffolds have great potential to promote cartilage repair effectively; this approach has become an area of considerable interest in recent investigations. Of late, an increasing trend was observed in cartilage tissue engineering towards this combination to develop a controlled delivery system that provides adequate physical support for neo-cartilage formation and also enables spatiotemporally delivery of growth factors to precisely and fully exert their chondrogenic potential. This review will discuss the role of polymer scaffolds and various growth factors involved in cartilage tissue engineering. Several growth factor delivery strategies based on the polymer scaffolds will also be discussed, with examples from recent studies highlighting the importance of spatiotemporal strategies for the controlled delivery of single or multiple growth factors in cartilage tissue engineering applications., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Chen et al.)

Biomimetic hydrogels have emerged as the most useful tissue engineering scaffold materials. Their versatile chemistry can recapitulate multiple physical and chemical features to integrate cells, scaffolds, and signaling molecules for tissue regeneration. Due to their highly hydrophilic nature hydrogels can recreate nutrient-rich aqueous environments for cells. Soluble regulatory molecules can be incorporated to guide cell proliferation and differentiation. Importantly, the controlled dynamic parameters and spatial distribution of chemical cues in hydrogel scaffolds are critical for cell-cell communication, cell-scaffold interaction, and morphogenesis. Herein, we review biomimetic hydrogels that provide cells with spatiotemporally controlled chemical cues as tissue engineering scaffolds. Specifically, hydrogels with temporally controlled growth factor-release abilities, spatially controlled conjugated bioactive molecules/motifs, and targeting delivery and reload properties for tissue engineering applications are discussed in detail. Examples of hydrogels that possess clinically favorable properties, such as injectability, self-healing ability, stimulus-responsiveness, and pro-remodeling features, are also covered.