| 1. |
- Akouri, Randa R., et al.
(författare)
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First live birth after uterus transplantation in the Middle East
- 2020
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Ingår i: Middle East Fertility Society Journal. - : Springer Science and Business Media LLC. - 1110-5690 .- 2090-3251. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The first live birth after uterus transplantation took place in Sweden in 2014. It was the first ever cure for absolute uterine factor infertility. We report the surgery, assisted reproduction, and pregnancy behind the first live birth after uterus transplantation in the Middle East, North Africa, and Turkey (MENAT) region. A 24-year old woman with congenital absence of the uterus underwent transplantation of the uterus donated by her 50-year-old multiparous mother. In vitro fertilization was performed to cryopreserve embryos. Both graft retrieval and transplantation were performed by laparotomy. Donor surgery included isolation of the uterus, together with major uterine arteries and veins on segments of the internal iliac vessels bilaterally, the round ligaments, and the sacrouterine ligaments, as well as with bladder peritoneum. Recipient surgery included preparation of the vaginal vault, end-to-side anastomosis to the external iliac arteries and veins on each side, and then fixation of the uterus. Results One in vitro fertilization cycle prior to transplantation resulted in 11 cryopreserved embryos. Surgical time of the donor was 608 min, and blood loss was 900 mL. Cold ischemia time was 85 min. Recipient surgical time was 363 min, and blood loss was 700 mL. Anastomosis time was 105 min. Hospital stay was 7 days for both patients. Ten months after the transplantation, one previously cryopreserved blastocyst was transferred which resulted in viable pregnancy, which proceeded normally (except for one episode of minor vaginal bleeding in the 1st trimester) until cesarean section at 35 + 1 weeks due to premature contractions and shortened cervix. A healthy girl (Apgar 9-10-10) weighing 2620 g was born in January 2020, and her development has been normal during the first 6 months. Conclusions This is the first report of a healthy live birth after uterus transplantation in the MENAT region. We hope that this will motivate further progress and additional clinical trials in this area in the Middle East Region, where the first uterus transplantation attempt ever, however unsuccessful, was performed already three decades ago.
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| 2. |
- Alshaikh, Ahmed Baker, et al.
(författare)
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Decellularization and recellularization of the ovary for bioengineering applications; studies in the mouse.
- 2020
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Ingår i: Reproductive biology and endocrinology : RB&E. - : Springer Science and Business Media LLC. - 1477-7827. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Fertility preservation is particularly challenging in young women diagnosed with hematopoietic cancers, as transplantation of cryopreserved ovarian cortex in these women carries the risk for re-introducing cancer cells. Therefore, the construction of a bioengineered ovary that can accommodate isolated small follicles was proposed as an alternative to minimize the risk of malignancy transmission. Various options for viable bioengineered scaffolds have been reported in the literature. Previously, we reported three protocols for producing mouse ovarian scaffolds with the decellularization technique. The present study examined these scaffolds further, specifically with regards to their extracellular composition, biocompatibility and ability to support recellularization with mesenchymal stem cells.Three decellularization protocols based on 0.5% sodium dodecyl sulfate (Protocol 1; P1), or 2% sodium deoxycholate (P2), or a combination of the two detergents (P3) were applied to produce three types of scaffolds. The levels of collagen, elastin and sulfated glycosaminoglycans (sGAGs) were quantified in the remaining extracellular matrix. Detailed immunofluorescence and scanning electron microscopy imaging were conducted to assess the morphology and recellularization efficiency of the constructs after 14days in vitro utilizing red fluorescent protein-labelled mesenchymal stem cells.All protocols efficiently removed the DNA while the elastin content was not significantly reduced during the procedures. The SDS-protocol (P1) reduced the sGAG and the collagen content more than the SDC-protocol (P2). All scaffolds were biocompatible and recellularization was successful, particularly in several P2-derived scaffolds. The cells were extensively distributed throughout the constructs, with a denser distribution observed towards the ovarian cortex. The cell density was not significantly different (400 to 550 cells/mm2) between scaffold types. However, there was a tendency towards a higher cell density in the SDC-derived constructs. Scanning electron microscope images showed fibrous scaffolds with a dense repopulated surface structure.While there were differences in the key structural macromolecules between protocols, all scaffolds were biocompatible and showed effective recellularization. The results indicate that our SDC-protocol might be better than our SDS-protocol. However, additional studies are necessary to determine their suitability for attachment of small follicles and folliculogenesis.
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| 3. |
- Alshaikh, Ahmed Baker, et al.
(författare)
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Decellularization of the mouse ovary: comparison of different scaffold generation protocols for future ovarian bioengineering.
- 2019
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Ingår i: Journal of ovarian research. - : Springer Science and Business Media LLC. - 1757-2215. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- In order to preserve fertility in young women with disseminated cancer, e.g. leukemia, an approach that has been suggested is to retransplant isolated small follicles within an ovarian matrix free from malignant cells and with no risk for contamination. The present study evaluates the first step to create a bioengineered ovarian construct that can act as growth-supporting tissue for isolated small follicles that are dependent on a stroma for normal follicular maturation. The present study used the intact mouse ovary to develop a mouse ovarian scaffold through various protocols of decellularization.Potential Immunogenic DNA and intracellular components were removed from whole mouse ovaries by agitation in a 0.5% sodium dodecyl sulfate solution (Protocol 1; P1), or in a 2% sodium deoxycholate solution (P2) or by a combination of the two (P3). The remaining decelluralized ovarian extracellular matrix structure was then assessed based on the DNA- and protein content, and was further evaluated histologically by haematoxylin and eosin-, Verhoeff's van gieson- (for elastin), Masson's trichrome- (for collagens) and Alcian blue (for glycosaminoglycans) staining. We also evaluated the decellularization efficiency using the mild detergent Triton-X100 (1%).Sodium dodecyl sulfate efficiently removed DNA and intracellular components from the ovarian tissue but also significantly reduced the integrity of the remaining ovarian extracellular matrix. Sodium deoxycholate, a considerably milder detergent compared to sodium dodecyl sulfate, preserved the ovarian extracellular matrix better, evident by a more distinct staining for glycosaminoglycan, collagen and elastic fibres. Triton-X100 was found ineffective as a decellularization reagent for mouse ovaries in our settings.The sodium dodecyl sulfate generated ovarian scaffolds contained minute amounts of DNA that may be an advantage to evade a detrimental immune response following engraftment. The sodium deoxycholate generated ovarian scaffolds had higher donor DNA content, yet, retained the extracellular composition better and may therefore have improved recellularization and other downstream bioengineering applications. These two novel types of mouse ovarian scaffolds serve as promising scaffold-candidates for future ovarian bioengineering experiments.
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| 4. |
- Brännström, Mats, 1958, et al.
(författare)
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Evolution of surgical steps in robotics-assisted donor surgery for uterus transplantation: results of the eight cases in the Swedish trial.
- 2020
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Ingår i: Fertility and sterility. - : Elsevier BV. - 1556-5653 .- 0015-0282. ; 114:5, s. 1097-1107
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Tidskriftsartikel (refereegranskat)abstract
- To perform a stepwise development of the surgical method for robotics-assisted laparoscopy in donor hysterectomy for uterus transplantation (UTx), a unique treatment for absolute uterine-factor infertility.Prospective observational study.University hospital.Eight donors, aged 38-62 years, underwent surgery for retrieval of the uterus and vasculature.Robotics-assisted laparoscopy was performed in donors for 6-7 h with video recording. Conversion to laparotomy was performed for last parts of retrieval surgery.Description, evaluation, and timing of 12 specific surgical steps, as well as surgical outcomes and complications.There was a progression during the course of eight surgeries. In the initial two cases, seven and six items were completed with robotics compared with all 12 items in the last three procedures. The passive surgical time decreased from ∼20% in the first four cases to ∼8% in the last three procedures. The estimated median (range) blood loss, total surgical time, and length of hospital stay were, respectively, 125 mL (100-600), 11.25 h (10-13), and 5.5 days (5-6). Two reversible complications occurred: One patient acquired pressure alopecia, and one developed pyelonephritis.The study demonstrates a clear evolution of a strategy toward fully robotic donor surgery in UTx. This is likely to become the main approach in donor surgery of live UTx donors.NCT02987023.
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| 5. |
- Brännström, Mats, 1958, et al.
(författare)
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Outcome of Recipient Surgery and 6-Month Follow-Up of the Swedish Live Donor Robotic Uterus Transplantation Trial.
- 2020
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Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Uterus transplantation has proved to be a feasible treatment for uterine factor infertility. Herein, we report on recipient outcome in the robotic uterus transplantation trial of 2017-2019. The eight recipients had congenital uterine aplasia. The donors were six mothers, one sister, and one family friend. Donor surgery was by robotic-assisted laparoscopy. Recipient surgery was by laparotomy and vascular anastomoses to the external iliacs. The duration (median (ranges)) of recipient surgery, blood loss, measured (left/right) uterine artery blood flow after reperfusion, and length of hospital stay were 5.15 h (4.5-6.6), 300 mL (150-600), 43.5 mL/min (20-125)/37.5 mL/min (10-98), and 6 days (5-9), respectively. Postoperative uterine perfusion evaluated by color Doppler showed open anastomoses but restricted blood distribution in two cases. Repeated cervical biopsies in these two cases initially showed ischemia and, later, necrosis. Endometrial growth was not seen, and hysterectomy was later performed, with pathology showing partly viable myometrium and fibrosis but necrosis towards the cavity. The other six patients acquired regular menstrual cyclicity. Surgery was performed in two patients to correct vaginal stenosis. Reversible rejection episodes were seen in two patients. In conclusion, the rate of viable uterine grafts during the initial 6-months of the present study (75%) leaves room for improvement in the inclusion/exclusion criteria of donors and in surgical techniques. Initial low blood flow may indicate subsequent graft failure.
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| 6. |
- Brännström, Mats, 1958, et al.
(författare)
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Reproductive, obstetric, and long-term health outcome after uterus transplantation: results of the first clinical trial
- 2022
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 0015-0282 .- 1556-5653. ; 118:3, s. 576-585
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate reproductive, obstetric, and long-term health of the first completed study of uterus transplantation (UTx). Design: Prospective. Setting: University hospital. Patient(s): Nine live donor UTx procedures were conducted and seven were successful. Donors, recipients, and children born were observed. Intervention(s): In vitro fertilization was performed with embryo transfer (ET) of day 2 or day 5 embryos in natural cycles. Pregnancies and growth trajectory of the children born were observed. Health-related quality of life, psychosocial outcome, and medical health of donors and recipients were evaluated by questionnaires. Main Outcome Measure(s): The results of in vitro fertilization, pregnancies, growth of children, and long-term health of patients were reported. Result(s): Six women delivered nine infants, with three women giving birth twice (cumulative birth rates of 86% and 67% in surgically successful and performed transplants, respectively). The overall clinical pregnancy rate (CPR) and live birth rate (LBR) per ET were 32.6% and 19.6%, respectively. For day 2 embryos, the CPR and LBR per ET were 12.5% and 8.6%, respectively. For day 5 embryos, the CPR and LBR per ET were 81.8% and 45.4%, respectively. Fetal growth and blood flow were normal in all pregnancies. Time of delivery (median in full pregnancy weeks + days [ranges]) by cesarean section and weight deviations was 35 + 3 (31 + 6 to 38 + 0) and -1% (-13% to 23%), respectively. Three women developed preeclampsia and four neonates acquired respiratory distress syndrome. All children were healthy and followed a normal growth trajectory. Measures of long-term health in both donors and recipients were noted to be favorable. When UTx resulted in a birth, scores for anxiety, depression, and relationship satisfaction were reassuring for both the donors and recipients. Conclusion(s): The results of this first complete UTx trial show that this is an effective infertility treatment, resulting in births of healthy children and associated with only minor psychological and medical long-term effects for donors and recipients. Clinical Trial Registration Number: NCT02987023.
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| 7. |
- Hellström, Mats, et al.
(författare)
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Towards the development of a bioengineered uterus : Comparison of different protocols for rat uterus decellularization
- 2014
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Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1742-7061 .- 1878-7568. ; 10:12, s. 5034-5042
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Tidskriftsartikel (refereegranskat)abstract
- Uterus transplantation (UTx) may be the only possible curative treatment for absolute uterine factor infertility, which affects 1 in every 500 females of fertile age. We recently presented the 6-month results from the first clinical UTx trial, describing nine live-donor procedures. This routine involves complicated surgery and requires potentially harmful immune suppression to prevent rejection. However, tissue engineering applications using biomaterials and stem cells may replace the need for a live donor, and could prevent the required immunosuppressive treatment. To investigate the basic aspects of this, we developed a novel whole-uterus scaffold design for uterus tissue engineering experiments in the rat. Decellularization was achieved by perfusion of detergents and ionic solutions. The remaining matrix and its biochemical and mechanical properties were quantitatively compared from using three different protocols. The constructs were further compared with native uterus tissue composition. Perfusion with Triton X-100/dimethyl sulfoxide/H2O led to a compact, weaker scaffold that showed evidence of a compromised matrix organization. Sodium deoxycholate/dH2O perfusion gave rise to a porous scaffold that structurally and mechanically resembled native uterus better. An innovative combination of two proteomic analyses revealed higher fibronectin and versican content in these porous scaffolds, which may explain the improved scaffold organization. Together with other important protocol-dependent differences, our results can contribute to the development of improved decellularization protocols for assorted organs. Furthermore, our study shows the first available data on decellularized whole uterus, and creates new opportunities for numerous in vitro and in vivo whole-uterus tissue engineering applications.
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| 8. |
- Humla, E. C., et al.
(författare)
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Summer is not associated with higher live birth rates in fresh IVF/ICSI cycles: a population-based nationwide registry study
- 2022
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Ingår i: Human Reproduction Open. - : Oxford University Press (OUP). - 2399-3529. ; 2022:4
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION Is summer associated with a higher live birth rate after fresh IVF/ICSI? SUMMARY ANSWER There was no support for a higher live birth rate after fresh IVF/ICSI when treatment was performed during the summer season. WHAT IS KNOWN ALREADY Seasonal variations in human natural conception and birth rates are well described. It has been hypothesized that serum vitamin D, levels of which are associated with sun exposure, may have a role in human natural conception rates. However, the association between seasons and IVF outcomes has not yet been clarified and conflicting reports have been published. Furthermore, it has been suggested that women with normal vitamin D levels have a better pregnancy outcome after ART compared to those with vitamin D insufficiency. STUDY DESIGN, SIZE, DURATION A nationwide, register-based cohort study including all first-time fresh IVF/ICSI treatments (n = 52 788) leading to oocyte retrieval in Sweden between 2009 and 2018 was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS All first-time fresh IVF/ICSI cycles leading to oocyte retrieval were identified in the National Quality Registry of Assisted Reproduction. Data collected included patient characteristics as well as information about the treatment cycle and pregnancy outcome. The patients were divided into season subgroups, (summer, autumn, winter and spring) based on the date of oocyte retrieval. The primary outcome was live birth rate, which was defined as the number of live births per oocyte retrieval and embryo transfer (ET). Other outcomes included clinical pregnancy per ET and miscarriage per clinical pregnancy. Logistic regression with multiple imputation was performed to evaluate whether there was an association between season and IVF/ICSI outcomes, with summer as reference. Adjustments were made for woman's age, year of treatment, BMI, total FSH/hMG dose, type of treatment, fertilization type, embryonic stage at ET and number of embryos transferred. MAIN RESULTS AND THE ROLE OF CHANCE Live birth rate per oocyte retrieval ranged between 24% and 26% among seasons. A significantly higher live birth rate was seen for spring compared with summer, 26% versus 24%, respectively (adjusted odds ratio (OR) 1.08, 95% CI 1.02-1.16, P = 0.02). No significant association was seen when winter and autumn were compared with summer. Live birth rate per ET ranged between 29% and 31% among seasons. A significantly higher live birth rate was seen for spring and autumn compared with summer, at 31% and 31%, respectively versus 29% (adjusted OR 1.08, 95% CI 1.01-1.16, P = 0.04 and adjusted OR 1.09, 95% CI 1.01-1.16, P = 0.02), respectively. No significant association was seen when winter was compared with summer. Clinical pregnancy rate varied between 36% and 38% and miscarriage rate between 16% and 18%, with no significant seasonal associations. LIMITATIONS, REASONS FOR CAUTION Possible limitations are the retrospective design of the study and unmeasured confounders. Another limitation is that a generalized estimating equation (GEE) model was not used. The use of a GEE model would have made it possible to include all started fresh IVF/ICSI cycles since it allows for correction for any dependence between cycles within women. WIDER IMPLICATIONS OF THE FINDINGS The results of this large registry study give no support for the hypothesis that IVF/ICSI treatments performed during summer season, with the highest degree of sunlight and vitamin D synthesis, is associated with higher pregnancy and live birth rates. In fact, our results showed significantly lower live birth rates during summer compared with spring and autumn. However, the magnitude of this difference was small and unlikely of clinical value. We suggest that season should not be taken into consideration when planning and performing fresh IVF/ICSI treatments. STUDY FUNDING/COMPETING INTEREST(S) Financial support was received through the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-70 940) and grants from the Hjalmar Svensson's Research Foundation (HJSV2021019 and HJSV2021037). None of the authors declare any conflict of interest.
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| 9. |
- Padma, Arvind M., et al.
(författare)
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Decellularization protocol-dependent damage-associated molecular patterns in rat uterus scaffolds differentially affect the immune response after transplantation.
- 2021
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Ingår i: Journal of tissue engineering and regenerative medicine. - : Hindawi Limited. - 1932-7005 .- 1932-6254. ; 15:7, s. 674-685
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Tidskriftsartikel (refereegranskat)abstract
- Scaffolds derived from decellularized tissue possess many advantages for bioengineering applications, including for novel infertility treatments. However, the decellularization process results in allogenic-independent damage-associated molecular patterns (DAMPs). This field is poorly studied, in particular for uterus bioengineering applications. An increased knowledge concerning the immune system activation after transplantation of decellularized tissue will enable safer construct development and thereby accelerate translation from research to clinic. We therefore transplanted rat uterus scaffolds produced by three different decellularization protocols based on Triton X-100 (P1 and P2) or sodium deoxycholate (P3) in a syngeneic animal model and assessed the immune response towards DAMPs exposed by the decellularization process. Biopsies were retrieved on day 5, 15, and 30 post transplantation and immunohistochemistry-stained CD45+ (leucocytes), CD4+ (T-cells), CD8a+ (cytotoxic T-cells), CD22+ (B-cells), NCR1+ (NK-cells), CD68+ (pan-macrophages), and CD163+ (M2 macrophages) cells within the grafts were quantified. The gene expression for interferon γ, interleukin (IL)-1β, IL-2, IL-6, and tumor necrosis factor (TNF) eotaxin-2, RANTES, MCP-1, MIP-1α, MIP-3α, IL-8 were also measured. Scaffolds from P1 induced a rapid cell infiltration after transplantation, presumably induced by DNA-based DAMPs. However, this response was only transient. Protocol 3 derived scaffolds induced an early pro-inflammatory cytokine response at the transcript level which remained high throughout the study. This response may be caused by the stronger decellularization detergent that could expose more extracellular matrix-related DAMPs. However, earlier proteomics analysis also identified significantly more abundant heat shook proteins-related DAMPs in this scaffold type. Protocol 2 caused the least immunogenic scaffolds and should thus be the future focus for in vivo uterus bioengineering applications.
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| 10. |
- Padma, Arvind M., et al.
(författare)
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Immune response after allogeneic transplantation of decellularized uterine scaffolds in the rat.
- 2021
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Ingår i: Biomedical Materials. - 1748-605X. ; 16:4
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Tidskriftsartikel (refereegranskat)abstract
- Data on how the immune system reacts to decellularized scaffolds after implantation is scarce and difficult to interpret due to many heterogeneous parameters such as tissue-type match, decellularization method and treatment application. The engraftment of these scaffolds must prove safe and that they remain inert to the recipient's immune system to enable successful translational approaches and potential future clinical evaluation. Herein, we investigated the immune response after the engraftment of three decellularized scaffold types that previously showed potential to repair a uterine injury in the rat. Protocol (P) 1 and P2 were based on Triton-X100 and generated scaffolds containing 820 ng mg-1and 33 ng mg-1donor DNA per scaffold weight, respectively. Scaffolds obtained with a sodium deoxycholate-based protocol (P3) contained 160 ng donor DNA per mg tissue. The total number of infiltrating cells, and the population of CD45+leukocytes, CD4+T-cells, CD8a+cytotoxic T-cells, CD22+B-cells, NCR1+NK-cells, CD68+and CD163+macrophages were quantified on days 5, 15 and 30 after a subcutaneous allogenic (Lewis to Sprague Dawley) transplantation. Gene expression for the pro-inflammatory cytokines INF-γ, IL-1β, IL-2, IL-6 and TNF were also examined. P1 scaffolds triggered an early immune response that may had been negative for tissue regeneration but it was stabilized after 30 d. Conversely, P3 initiated a delayed immune response that appeared negative for scaffold survival. P2 scaffolds were the least immunogenic and remained similar to autologous tissue implants. Hence, an effective decellularization protocol based on a mild detergent was advantageous from an immunological perspective and appears the most promising for futurein vivouterus bioengineering applications.
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