Journal of Tissue Engineering and Regenerative Medicine最新文献

{"title":"Selective kidney targeting increases the efficacy of mesenchymal stromal/stem cells for alleviation of murine stenotic-kidney senescence and damage","authors":"Seo Rin Kim,&nbsp;Kai Jiang,&nbsp;Xiaojun Chen,&nbsp;Amrutesh S. Puranik,&nbsp;Xiang-Yang Zhu,&nbsp;Amir Lerman,&nbsp;Tamara Tchkonia,&nbsp;James L. Kirkland,&nbsp;Lilach O. Lerman","doi":"10.1002/term.3299","DOIUrl":"https://doi.org/10.1002/term.3299","url":null,"abstract":"<p>Chronic ischemia triggers senescence in renal tubules and at least partly mediates kidney dysfunction and damage through a <i>p16</i>^<i>Ink4a</i>-related mechanism. We previously showed that mesenchymal stromal/stem cells (MSCs) delivered systemically do not effectively decrease cellular senescence in stenotic murine kidneys. We hypothesized that selective MSC targeting to injured kidneys using an anti-KIM1 antibody (KIM-MSC) coating would enhance their ability to abrogate cellular senescence in murine renal artery stenosis (RAS). KIM-MSC were injected into transgenic <i>INK-ATTAC</i> mice, which are amenable for selective eradication of <i>p16</i>^{<i>Ink4a+</i>} cells, 4 weeks after induction of unilateral RAS. To determine whether KIM-MSC abolish <i>p16</i>^<i>Ink4a</i>-dependent cellular senescence, selective clearance of <i>p16</i>^{<i>Ink4a+</i>} cells was induced in a subgroup of RAS mice using AP20187 over 3 weeks prior to KIM-MSC injection. Two weeks after KIM-MSC aortic injection, renal senescence, function, and tissue damage were assessed. KIM-MSC delivery decreased gene expression of senescence and senescence-associated secretory phenotype factors, and improved micro-MRI-derived stenotic-kidney glomerular filtration rate and perfusion. Renal fibrosis and tubular injury also improved after KIM-MSC treatment. Yet, their efficacy was slightly augmented by prior elimination of <i>p16</i>^{<i>Ink4a+</i>} senescent cells. Therefore, selective targeting of MSC to the injured kidney markedly improves their senolytic potency in murine RAS, despite incomplete eradication of p16⁺ cells. KIM-MSC may constitute a useful therapeutic strategy in chronic renal ischemic injury.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 6","pages":"550-558"},"PeriodicalIF":3.3,"publicationDate":"2022-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/term.3299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5687199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A composite bilayer scaffold functionalized for osteochondral tissue regeneration in rat animal model","authors":"Shabnam Abedin Dargoush,&nbsp;Hana Hanaee-Ahvaz,&nbsp;Shiva Irani,&nbsp;Masoud Soleimani,&nbsp;Seyedeh Mahsa Khatami,&nbsp;Alireza Naderi Sohi","doi":"10.1002/term.3297","DOIUrl":"https://doi.org/10.1002/term.3297","url":null,"abstract":"<p>Osteochondral defects are defined most typically by damages to both cartilage and subchondral bone tissue. It is challenging to develop bilayered scaffolds that regenerate both of these lineages simultaneously. In the present study, an electrospun bilayer nanofibrous scaffold was designed to repair osteochondral lesions. A nanocomposite of hydroxyapatite, strontium, and reduced graphene oxide were combined with polycaprolactone polymer to fabricate the osteogenic differentiation layer. Additionally, the chondrogenic differentiation layer was also formed using polyethersulfone polymer and benzyl hyaluronan. The physical, mechanical, and chemical properties of the scaffolds were determined, and adipose-derived mesenchymal stem cells were cultured on each layer to evaluate their biocompatibility and differentiation potential. Cell viability, mineralization, <i>alkaline phosphatase enzyme (ALP)</i> expression, and extracellular calcium deposition were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, alizarin red staining, ALP activity, and calcium deposition. Real-time polymerase chain reaction (PCR) was used to assess the expression levels of osteogenic (<i>Collagen I, Runx II, ALP, Osteocalcin</i>) and chondrogenic (<i>Sox9, Collagen II (Col II), Aggrecan</i>) genes. Finally, the osteochondral scaffold was created by electrospinning these two layers for 2 days. The scaffold was grafted into the osteochondral defect of a Wistar rat's knee. 60 days after surgery, real-time PCR, immunohistochemistry (IHC), and hematoxylin and eosin staining were performed. The expression of chondrogenic and osteogenic genes was increased compared to the control group, as confirmed by real-time PCR. Furthermore, IHC revealed a rise in <i>Col II</i> and <i>Collagen X</i> expression. Finally, in vivo and in vitro studies have shown that the electrospun bilayer scaffold is biocompatible, which facilitates osteochondral healing.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 6","pages":"559-574"},"PeriodicalIF":3.3,"publicationDate":"2022-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6004750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient genetic engineering of murine cochlear organoids","authors":"Yan Zhang,&nbsp;Xiu-Li Hao,&nbsp;Shi-Fang Jia,&nbsp;Yan-Zhen Wen,&nbsp;Ying-Hui Wang","doi":"10.1002/term.3298","DOIUrl":"https://doi.org/10.1002/term.3298","url":null,"abstract":"<p>Organoid culture is a popular model to study gene function as the easy manipulating and time saving compared with <i>in vivo</i> experiments. This is widely used in auditory system for studying supporting cells (SCs) or hair cells (HCs) as only very few SCs or HCs can be harvested in both human and murine cochlea. However, the use of organoids is still a challenge due to the low efficiency in genetic modification. Here we took <i>Lin28b</i> as an example and compared <i>Lin28b</i> gain-of-function (GOF) and loss-of-function (LOF) with different genetic engineering methods and found that TetOn induced GOF or LOF was more efficient compared with lipofection or lentiviral transduction in the experimental conditions we used. Cell apoptosis in TetOn induction system was lowest compared with the other methods in this study. Our study is the first to compare the efficiency of different genetic engineering techniques in cochlear organoid culture, which may also apply to organoids established with other tissues.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 6","pages":"530-537"},"PeriodicalIF":3.3,"publicationDate":"2022-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5932682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transposon-mediated glial cell line-derived neurotrophic factor overexpression in human adipose tissue-derived mesenchymal stromal cells: A potential approach for neuroregenerative medicine?","authors":"Justyna Rasińska,&nbsp;Charlotte Klein,&nbsp;Laura Stahn,&nbsp;Felix Maidhof,&nbsp;Anna Pfeffer,&nbsp;Stefanie Schreyer,&nbsp;Manfred Gossen,&nbsp;Andreas Kurtz,&nbsp;Barbara Steiner,&nbsp;Shabnam Hemmati-Sadeghi","doi":"10.1002/term.3296","DOIUrl":"https://doi.org/10.1002/term.3296","url":null,"abstract":"<p>Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective effects and may be a promising candidate for regenerative strategies focusing on neurodegenerative diseases. As GDNF cannot cross the blood–brain barrier to potentially regenerate damaged brain areas, continuous in situ delivery with host cells is desired. Here, a non-viral Sleeping Beauty transposon was used to achieve continuous in vitro overexpression of GDNF in immune-privileged human adipose tissue-derived mesenchymal stromal cells (GDNF-tASCs). In addition, in vivo survival, tolerance, and effectiveness of transfected cells were tested in a very mild 6-hydroxydopamine (6-OHDA)-induced dopamine depletion rat model by means of intrastriatal injection on a sample basis up to 6 months after treatment. GDNF-tASCs showed vast in vitro gene overexpression up to 13 weeks post-transfection. In vivo, GDNF was detectable 4 days following transplantation, but no longer after 1 month, although adipose tissue-derived mesenchymal stromal cells (ASCs) could be visualized histologically even after 6 months. Despite successful long-term in vitro GDNF overexpression and its in vivo detection shortly after cell transplantation, the 6-OHDA model was too mild to enable sufficient evaluation of in vivo disease improvement. Still, in vivo immunocompatibility could be further examined. ASCs initially induced a pronounced microglial accumulation at transplantation site, particularly prominent in GDNF-tASCs. However, 6-OHDA-induced pro-inflammatory immune response was attenuated by ASCs, although delayed in the GDNF-tASCs group. To further test the therapeutic potential of the generated GDNF-overexpressing cells in a disease-related context, a follow-up study using a more appropriate 6-OHDA model is needed.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 6","pages":"515-529"},"PeriodicalIF":3.3,"publicationDate":"2022-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/term.3296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5826667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pro-angiogenic potential of a functionalized hydrogel scaffold as a secretome delivery platform: An innovative strategy for cell homing-based dental pulp tissue engineering","authors":"Giovanna Lopes Carvalho,&nbsp;Giovanna Sarra,&nbsp;Gabriella Torres Schr?ter,&nbsp;Linda Sarah Reis Gomes Silva,&nbsp;Suely Kunimi Kubo Ariga,&nbsp;Flávia Gon?alves,&nbsp;Hector Valentin Caballero-Flores,&nbsp;Maria Stella Moreira","doi":"10.1002/term.3294","DOIUrl":"https://doi.org/10.1002/term.3294","url":null,"abstract":"<p>Angiogenesis is a key process that provides a suitable environment for successful tissue engineering and is even more crucial in regenerative endodontic procedures, since the root canal anatomy limits the development of a vascular network supply. Thus, sustainable and accelerated vascularization of tissue-engineered dental pulp constructs remains a major challenge in cell homing approaches. This study aimed to functionalize a chitosan hydrogel scaffold (CS) as a platform loaded with secretomes of stem cells from human exfoliated deciduous teeth (SHEDs) and evaluate its bioactive function and pro-angiogenic properties. Initially, the CS was loaded with SHED secretomes (CS-S), and the release kinetics of several trophic factors were assessed. Proliferation and chemotaxis assays were performed to analyze the effect of functionalized scaffold on stem cells from apical papilla (SCAPs) and the angiogenic potential was analyzed through the Matrigel tube formation assay with co-cultured of human umbilical vein endothelial cells and SCAPs. SHEDs and SCAPs expressed typical levels of mesenchymal stem cell surface markers. CS-S was able to release the trophic factors in a sustained manner, but each factor has its own release kinetics. The CS-S group showed a significantly higher proliferation rate, accelerated the chemotaxis, and higher capacity to form vascular-like structures. CS-S provided a sustained and controlled release of trophic factors, which, in turn, improved proliferation, chemotaxis and all angiogenesis parameters in the co-culture. Thus, the functionalization of chitosan scaffolds loaded with secretomes is a promising platform for cell homing-based tissue engineering.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 5","pages":"472-483"},"PeriodicalIF":3.3,"publicationDate":"2022-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5699976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and development of thyroxine/heparin releasing affordable cotton dressings to treat chronic wounds","authors":"Tayyba Sher Waris,&nbsp;Syed Tahir Abbas Shah,&nbsp;Azra Mehmood,&nbsp;Zohaib Iqbal,&nbsp;Mubashra Zehra,&nbsp;Aqif Anwar Chaudhry,&nbsp;Ihtesham Ur Rehman,&nbsp;Muhammad Yar","doi":"10.1002/term.3295","DOIUrl":"https://doi.org/10.1002/term.3295","url":null,"abstract":"<p>This research on a thyroxine/heparin-based cotton wound dressing tests angiogenic and wound healing ability of thyroxine/heparin in a chick chorionic allantoic membrane bioassay and in skin wounds in healthy rats. Commercially available cotton dressings were simply loaded with thyroxine/heparin solutions and coated with wax. Prior to undertaking the animal study, we assessed in vitro release of thyroxine/heparin from coated and uncoated cotton dressings. Both showed more than 85% release of drug over 14 days, though the lesser release was observed in wax-coated thyroxine/heparin dressing as compared to uncoated thyroxine/heparin dressing. Testing of angiogenesis through CAM assay proved good angiogenic potential of heparin and thyroxin, but the thyroxine found more angiogenic than heparin. In animal study, full-thickness skin wounds of 20 mm diameter showed good healing in both heparin and thyroxine-treated groups. But the most striking result was seen in the thyroxine-treated group where thyroxine showed significant difference with heparin-treated group and completely healed the wounds in 23 days. Thus, the study suggest that thyroxine possesses greater angiogenic and wound healing potential than heparin, and the use of thyroxine/heparin-loaded wax-coated cotton dressing could be a cost-effective option for the management of chronic wounds.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 5","pages":"460-471"},"PeriodicalIF":3.3,"publicationDate":"2022-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5699975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myoblast 3D bioprinting to burst in vitro skeletal muscle differentiation","authors":"Flavio L. Ronzoni,&nbsp;Flaminia Aliberti,&nbsp;Franca Scocozza,&nbsp;Laura Benedetti,&nbsp;Ferdinando Auricchio,&nbsp;Maurilio Sampaolesi,&nbsp;Gabriella Cusella,&nbsp;Itedale Namro Redwan,&nbsp;Gabriele Ceccarelli,&nbsp;Michele Conti","doi":"10.1002/term.3293","DOIUrl":"https://doi.org/10.1002/term.3293","url":null,"abstract":"<p>Skeletal muscle regeneration is one of the major areas of interest in sport medicine as well as trauma centers. Three-dimensional (3D) bioprinting (BioP) is nowadays widely adopted to manufacture 3D constructs for regenerative medicine but a comparison between the available biomaterial-based inks (bioinks) is missing. The present study aims to assess the impact of different hydrogels on the viability, proliferation, and differentiation of murine myoblasts (C2C12) encapsulated in 3D bioprinted constructs aided to muscle regeneration. We tested three different commercially available hydrogels bioinks based on: (1) gelatin methacrylate and alginate crosslinked by UV light; (2) gelatin methacrylate, xanthan gum, and alginate-fibrinogen; (3) nanofibrillated cellulose (NFC)/alginate-fibrinogen crosslinked with calcium chloride and thrombin. Constructs embedding the cells were manufactured by extrusion-based BioP and C2C12 viability, proliferation, and differentiation were assessed after 24 h, 7, 14, 21, and 28 days in culture. Although viability, proliferation, and differentiation were observed in all the constructs, among the investigated bioinks, the best results were obtained by using NFC/alginate-fibrinogen-based hydrogel from 7 to 14 days in culture, when the embedded myoblasts started fusing, forming at day 21 and day 28 multinucleated myotubes within the 3D bioprinted structures. The results revealed an extensive myotube alignment all over the linear structure of the hydrogel, demonstrating cell maturation, and enhanced myogenesis. The bioprinting strategies that we describe here denote a strong and endorsed approach for the creation of in vitro artificial muscle to improve skeletal muscle tissue engineering for future therapeutic applications.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 5","pages":"484-495"},"PeriodicalIF":3.3,"publicationDate":"2022-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/term.3293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6077028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of electrical stimulation on cytokine-induced macrophage polarization","authors":"Jiahao Gu,&nbsp;Xuzhao He,&nbsp;Xiaoyi Chen,&nbsp;Lingqing Dong,&nbsp;Wenjian Weng,&nbsp;Kui Cheng","doi":"10.1002/term.3292","DOIUrl":"https://doi.org/10.1002/term.3292","url":null,"abstract":"<p>Macrophages have two functionalized phenotypes, M1 and M2, and the regulation of M1/M2 polarization of macrophages is critical for tissue repair. Tissue-derived immune factors are considered the major drivers of macrophage polarization. Based on the main cytokine-induced polarization pathways, we tested the effect of electrical stimulation (ES) of macrophages on the regulation of M1/M2 polarization and a possible synergistic effect with the cytokines. Indium tin oxide (ITO) planar microelectrodes were used to produce ES under different voltages, frequencies and waveforms. We evaluated the influence of ES on the cytokine-induced M1/M2 polarization using mouse bone marrow-derived macrophages cultured with both lipopolysaccharide (LPS)/IFN-γ factors and IL-4 factors for M1 and M2, respectively. The results showed that ES promoted the cytokine-induced macrophage polarization. Importantly, we found that stimulation with a square waveform selectively promoted LPS/IFN-γ-induced M1 polarization, while stimulation with a sinusoidal waveform promoted both LPS/IFN-γ-induced M1, and IL-4-induced M2 polarization. Mechanistically, stimulation with a square waveform affected the intracellular ion concentration, whereas stimulation with a sinusoidal waveform promoted both the intracellular ion concentration and membrane receptors. We hereby establish an ES-mediated strategy for immunomodulation via macrophage polarization.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 5","pages":"448-459"},"PeriodicalIF":3.3,"publicationDate":"2022-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5752154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guiding bone formation using semi-onlay calcium phosphate implants in an ovine calvarial model","authors":"Gry Hulsart Billstr?m,&nbsp;Viviana R. Lopes,&nbsp;Christopher Illies,&nbsp;Sara Gallinetti,&nbsp;Jonas ?berg,&nbsp;H?kan Engqvist,&nbsp;Conrado Aparicio,&nbsp;Sune Larsson,&nbsp;Lars Kihlstr?m Burenstam Linder,&nbsp;Ulrik Birgersson","doi":"10.1002/term.3288","DOIUrl":"https://doi.org/10.1002/term.3288","url":null,"abstract":"<p>The restoration of cranio-maxillofacial deformities often requires complex reconstructive surgery in a challenging anatomical region, with abnormal soft tissue structures and bony deficits. In this proof-of-concept, the possibility of vertical bone augmentation was explored by suspending hemispherically shaped titanium-reinforced porous calcium phosphate (CaP) implants (<i>n</i> = 12) over the frontal bone in a sheep model (<i>n</i> = 6). The animals were euthanized after week 13 and the specimens were subject to micro-computed tomography (μCT) and comprehensive histological analysis. Histology showed that the space between implant and the recipient bone was filled with a higher percentage of newly formed bone (NFB) versus soft tissue with a median of 53% and 47%, respectively. Similar results were obtained from the μ-CT analysis, with a median of 56% NFB and 44% soft tissue filling the void. Noteworthy, significantly higher bone-implant contact was found for the CaP (78%, range 14%–94%) versus the Titanium (29%, range 0%–75%) portion of the implant exposed to the surrounding bone. The histological analysis indicates that the CaP replacement by bone is driven by macrophages over time, emphasized by material-filled macrophages found in close vicinity to the CaP with only a small number of single osteoclasts found actively remodeling the NFB. This study shows that CaP based implants can be assembled with the help of additive manufacturing to guide vertical bone formation without decortification or administration of growth factors. Furthermore, it highlights the potential disadvantage of a seamless fit between the implant and the recipient's bone.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 5","pages":"435-447"},"PeriodicalIF":3.3,"publicationDate":"2022-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/term.3288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6001403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Filgrastim, fibrinolysis, and neovascularization","authors":"Darwin Eton,&nbsp;Guolin Zhou,&nbsp;Tong-Chuan He,&nbsp;Amelia Bartholomew,&nbsp;Rachana Patil","doi":"10.1002/term.3284","DOIUrl":"https://doi.org/10.1002/term.3284","url":null,"abstract":"<p>Segmental recanalization of chronically occluded arteries was observed in patients with chronic limb-threatening ischemia (CLTI) treated with Filgrastim, a granulocyte colony stimulating factor, every 72 h for up to a month, and an infra-geniculate programmed compression pump (PCP) for 3 h daily. Molecular evidence for fibrinolysis and neovascularization was sought. CLTI patients were treated with PCP alone (<i>N</i> = 19), or with Filgrastim and PCP (<i>N</i> = 8 and <i>N</i> = 6, at two institutions). Enzyme-Linked Immunosorbent Assay was used to measure the plasma concentration of plasmin and of fibrin degradation products (FDP), and the serum concentration of proteins associated with neovascularization. In the PCP-alone group, blood was sampled on Day 1 (baseline) and after 30 days of daily PCP. In the Filgrastim and PCP group, blood was drawn on Day 1, and 1 day after the 5th and the 10th Filgrastim doses. Each blood draw occurred before and after 2 h of supervised PCP. Significant (<i>p</i> &lt; 0.01) PCP independent increases in the plasma concentration of plasmin (&gt;10-fold) and FDP (&gt;5-fold) were observed 1 day after both the 5th and the 10th Filgrastim doses, compared to Day 1. Significant (<i>p</i> &lt; 0.05) increases in the concentration of pro-angiogenic proteins (e.g., HGF, MMP-9, VEGF A) were also observed. Filgrastim at this novel dosimetry induced fibrinolysis without causing acute hemorrhage, in addition to inducing a pro-angiogenic milieu conducive to NV. Further clinical testing is warranted at this novel dosimetry in CLTI, as well as in other chronically ischemic tissue beds.</p><p><b>Trial registration</b>. https://clinicaltrials.gov/ct2/show/NCT02802852.</p>","PeriodicalId":202,"journal":{"name":"Journal of Tissue Engineering and Regenerative Medicine","volume":"16 5","pages":"496-510"},"PeriodicalIF":3.3,"publicationDate":"2022-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/term.3284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5729466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}