Lee, R. H. et al. And the loss of MSCs in the colon may attribute to many reasons, such as, wash out, cell death, or even rejection via the innate immune system. volume6, Articlenumber:30696 (2016) Samples were prepared and tested as previously reported47. was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity . Two early reports aroused the global interests of stem cell transplantation in IBD management. Intramuscular. An improved mouse model of sepsis based on intraperitoneal injections of the enriched culture of cecum slurry . [citation needed]. In order to explore the possible mechanisms of these alterations, oxidative stress and inflammation levels in the mouse brain were examined. ISSN 2045-2322 (online). International journal of molecular medicine 37, 115125, doi: 10.3892/ijmm.2015.2413 (2016). These cells were confirmed as bone marrow MSCs using flow-cytometric analysis and differential identification (Supplementary Figures S1 and S2). Cells, tissues, organs 169, 1220 (2001). https://doi.org/10.1038/srep30696. 2020 May 9;12(5):439. doi: 10.3390/pharmaceutics12050439. It also shows how easily substances are absorbed through the peritoneal cavity after an IP injection. Thus, we have succeeded to produce patient-like tumor colonization of the peritoneal cavity and hepatic metastasis with the human EAC cell line OE19 by intraperitoneal injection in SCID mice. Small animals: 1 mL per 10 lb of body weight. These time-tested therapies may perform well on some patients, but also exhibit inadequacies in efficacy. Cosnes, J., Gower-Rousseau, C., Seksik, P. & Cortot, A. However, doubts exist over the use of Fe 3 O 4-nanoparticles in human beings. Article Though IP injection showed benefits in many human and animal studies, even recommend by National Cancer Institute (NCI) for advanced ovarian chemotherapy, it is more often applied to animals than to humans for the time being57. Furthermore, the corresponding mesentery lymph nodes (MLNs) also showed relatively high MSCs existence (Fig. Epidemiology and natural history of inflammatory bowel diseases. 2020 Jun 3;37(6):119. doi: 10.1007/s11095-020-02818-8. Free DiR and healthy mice (without colitis) were served as control. Google Scholar. Intraperitoneal but not intravenous cryopreserved mesenchymal stromal cells home to the inflamed colon and ameliorate experimental colitis. All experimental procedures performed were approved by Animal Welfare and Ethics Committee of the Fourth Military Medical University (FMMU), which are in accordance with the NIH guidelines. In view of these observations, and the fact that NASH is a The serum concentration of TNFinduced protein 6 (TSG-6) was measured in DSS colitic mice at 48 and 72hours after different routes of MSCs administrations. Chemotactic cytokines might be involved and responsible for MSCs attraction. Intraperitoneal Injection of Oncolytic Viruses H101 for Patients With Refractory Malignant Ascites. While the DiR labeled cells showed very different cell distribution. MSCs were isolated from C57BL/6 mice bone marrow as previously reported62. Article gynecological and gastrointestinal cancers and has shown very promising results. PubMed Central 3) and the IV group preserved fewer cell number. Human. Epub 2020 Mar 18. Review article: stem cell therapies for inflammatory bowel disease - efficacy and safety. From whole-body disease recovery, the amount of MSCs colons engraftment, tissue histological evaluation as well as levels of cytokines and TSG-6. In a case of a ruptured hepatocellular carcinoma, it was reported that the patient was treated successfully through the use of an intraperitoneal injection of OK-432, which is an immunomodulatory agent. In IP group, the MSCs existence can be detected at day 1, but gradually decreased with the time, GFP+ cells can be hardly identified in inflamed colon after day 3 (data not shown). . Article Vishnubalaji, R., Al-Nbaheen, M., Kadalmani, B., Aldahmash, A. (A) The colonic mRNA expression of TNF- and IL-10 was analyzed by RT-PCR; (B) cytokine contents in colonic protein extracts were determined by ELISA; n=6 mice/group; n=3 for the control group (C) Serum TSG-6 level in different groups measured by ELISA. Khalil, P. N. et al. Yu-Lung Chang, Huei-Yu Lo, Chin-Kan Chan, Xing-hua Pan, Qing-qing Li, Guang-ping Ruan, Hongsheng Yang, Rui Feng, Shenghong Zhang, H. R. Wardill, C. E. M. de Mooij, N. M. A. Blijlevens, Suze A. Jansen, Edward E. S. Nieuwenhuis, Caroline A. Lindemans, Scientific Reports MSCs induced more Ki-67 positive cells in the lower part of the crypt than the DSS control. Upon intravenous and intraperitoneal injection of stressed MSA, fluorescent "hotspots" were observed in the spleens, livers and lungs. (CS), Intraperitoneal, Polymicrobial, and Antibiotics available under aCC-BY 4.0 International license. The fecal occult blood test on the day 3 also showed nearly complete absence of occult blood in IP group. Of the time points we tested (6, 16, 24 h) our results showed that a 16-h post-intraperitoneal injection image scan provided the best contrast in mice regardless of age or disease burden. prepared Figure 4. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Horwitz, E. M. et al. Fresh feces from animals were collected for occult blood test, using fecal occult blood kit (Baso Diagnostics Inc., Zhuhai, China) according to the manufactures recommendations. and H.H. The data showed that the TSG-6 levels increased with time in both IP and IV injection groups, while in DSS control group, the TSG-6 level decreased from 48h to 72h. Although there is no significant difference among three injection groups at 48h after MSCs transplantation, the serum TSG-6 was significant higher in IP injection group compared with naive group (P=0.024). In this study, three different MSCs delivery routes, intraperitoneal injection (IP), intravenous injection (IV) and anal injection (AI) were compared on DSS-induced colitis mouse model. Bioengineered. GAPDH mRNA was used as an internal control to normalize mRNA expression. The ELISA kit for TNFinduced protein 6 was used (CUSABIO Life science, China). In IV group, the colon homing cells were fewer, most of MSCs were trapped in MSCs were rapidly accumulate into the lung and mononuclear phagocytic system. Easier to inject that intravenous. Collagen deposition limits immune reconstitution in the gut. Neutrophil infiltration was monitored by measuring MPO activity67. It can significant reduce failure puncture and associated organ damages caused by blind needle puncturing. L.Z. n=68 mice/group; n=3 for the control and naive (health mice) group. Thank you for visiting nature.com. B.X. By submitting a comment you agree to abide by our Terms and Community Guidelines. CAS Experiments with microspheres has showed that most of particle of this size would be clear out by the lung17. The results set a precedent of how other drugs may be delivered in this way to treat other similar medical issues after further research. Cell stem cell 9, 1115, doi: 10.1016/j.stem.2011.06.008 (2011). 2, Haidian District, Beijing 100193, China. Just mentioned above, immune cells and MSCs interaction in aggregates promotes TSG-6 secretion and contributed to the colitis recovery. Rodent (large / mouse) oral (intragastric), intravascular administration (tail vein injection, intraperitoneal injection, intramuscular injection and subcutaneous injection) Intragastric administration and oral taking of non-rodent (dog / monkey) solution and intravenous injection of extremities. In COX-2 blocking control experiments, mice received FA-NPs (0.5 mg/kg) 1 h after an intraperitoneal injection of celecoxib (10 mg/kg) to block binding of FA to the COX-2 active site. It means IP injection is more feasible and reasonable for clinical settings. From the overall appearance, the hyperemia and edema of the colon in all MSCs treatment groups became milder than the DSS control. Summers, R. W. Novel and future medical management of inflammatory bowel disease. sharing sensitive information, make sure youre on a federal [17] Contrast agents were administered intraperitoneally instead of intravenously to avoid errors and challenges. doi: 10.1002/14651858.CD005284.pub3. The fluorescence imaging disclosed higher intensity of engrafted cells in inflamed colon and the corresponding mesentery lymph nodes (MLNs) in IP and AI groups than the IV group. humans have been associated with clinical pain, inflammatory lesions, and abscess formation in . In anal injection group, same amount of cells were suspended in 200L diluted Matrigel in PBS (1:20) and the cell suspension was instilled into colonic lumen by a syringe with flexible catheter 4cm in length and 2mm in diameter, according to the previous study64. RNA was reverse transcribed using the iScript cDNA Synthesis Kit (Bio Rad, Hercules, CA). An official website of the United States government. of the needle exposed to assure 4-5mm injection depth. At 72h, the IP groups showed significant higher level of TSG-6 than AI groups and DSS control (P=0.023 and P=0.005, respectively). . Gastroenterology 136, 978989, doi: 10.1053/j.gastro.2008.11.041 (2009). Severity of DSS-induced colitis was also assessed using a score system by two independent pathologists. X.W., Y.H., Y.N. Select search scope, currently: articles+ all catalog, articles, website, & more in one search; catalog books, media & more in the Stanford Libraries' collections; articles+ journal articles & other e-resources PubMed Sirius red staining showed disorganized collagen fibers in DSS control colon, which were diffusely distributed in the injured colon wall. It is estimated that as many as 1.4million Americans and 2.4million Europeans are suffering from these diseases1,2. Intraperitoneal (IP) route of drug administration in laboratory animals is a common practice in many in vivo studies of disease models. The formation of the aggregates probably limits access of the cells to the systemic circulation. In consistence with PCR results, IP groups showed higher IL-10 and lower TNF- than other MSCs delivery ways (Fig. ADS This review discusses the usefulness of IP drug therapy and the factors influencing it, as well as strategies to increase the efficacy, and conclude that IP route is an alternate route to the more conventional drug delivery routes, and can be successfully used when the target is within the peritoneal cavity or adjacent tissue. The Scheme (Fig. Clinical Ovarian and Other Gynecologic Cancer 5, 2426, doi: 10.1016/j.cloc.2011.08.001 (2012). Intraperitoneal injection of a substance in the mouse. Cite this article. IP injection showed better amelioration of colitis and may be an ideal delivery way for MSCs in IBD therapy. The most efficient method to inject small animals is a two-person method where one holds the rodent and the other person injects the rodent at about 10 to 20 degrees in mice and 20 to 45 degrees in rats. Clinical and experimental immunology 116, 238245 (1999). [citation needed], In humans, the method is widely used to administer chemotherapy drugs to treat some cancers, particularly ovarian cancer. . The fecal occult blood test on the day 3 also showed nearly complete absence of occult blood in IP group (Figure 1D). 4 The scalp was disinfected and a midline incision was made in the skin. The first major problem with IV route is the pulmonary first-pass effects, which cause significant entrapment of cells15. 2021. Intraperitoneal injection (IP), Intravenous injection (IV) or anal injection (AI)? All the tissue sections in this study were scan and analyzed with Virtual slide scanning system (VS120-S, Olympus). Shariati M, Zhang H, Van de Sande L, Descamps B, Vanhove C, Willaert W, Ceelen W, De Smedt SC, Remaut K. Pharm Res. In their study, PKH26 (a yellow-orange fluorescent dye) labeled PCs were injected intraperitoneally into healthy rat. . PubMed Proper Method for Intraperitoneal Injections Total RNA was extracted with the RNAeasy Plus kit (QIAGEN). The number of therapeutic cells that can migrate and colonize at the injury site is a decisive prerequisite for the success of cytotherapy. The AI and IV showed no significant intergroup difference, though AI had lower score (Fig. One of the earliest recorded uses of IP injections involved the insemination of a guinea-pig in 1957. Li, C. Y. et al. & Dennis, J. E. MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies and Immune Modulation. We selected the day 3 as observation time point. Mice were made diabetic by intraperitoneal injection of streptozotocin, which led to a 2- to 2.5-fold increase in plasma glucose. Their findings showed that intraperitoneally injected MSCs would form aggregates with macrophages and lymphocytes in peritoneal cavity and remotely secreted TSG-6. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. Maximum 15 10 slow injection 10 2 (divided in 2-3 sites) 0.5 (Max 2 ml limit) Minipig Ideal 10 1-5 bolus 1 1 0.25 Maximum 15 10 slow injection 20 3 (divided in 2-3 sites) 0.5 (Max 5 ml limit per site) * Bolus injections are typically dosed in less than 1 minute. 2B). Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Increased initial cell dose ensures an increased number of cells that reach to the injury site. ADS Zhang, B. et al. The authors declare no competing financial interests. 4C). Statistical significance was determined using one-way ANOVAs or Students t tests. Indeed, Mariana et al. Our findings showed that the GFP+ MSCs were migrated to the inflamed colon, even passed through the whole intestinal wall and reached the luminal side. Intraperitoneal injection carries the risk of causing internal injury or of misplaced injection into a blood vessel or an organ, particularly the large thin-walled cecum or urinary bladder. East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort. Collagen deposition is another indicator for wound healing, however, extensive collagen deposition may hamper the gut reconstitution14. Samples were frozen and thawed 3 times, centrifuged at 30,000g for 20minutes. [5] In 1967, the production of amnesia was studied through an injection of physostigmine. World journal of gastroenterology 20, 1822818239, doi: 10.3748/wjg.v20.i48.18228 (2014). The Ki-67+ cells were greatly increased after MSCs treatment. Evid Based Complement Alternat Med. Augello, A., Tasso, R., Negrini, S. M., Cancedda, R. & Pennesi, G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. The IP technique is an easy technique to master. Course of Crohns disease after allogeneic marrow transplantation. eCollection 2021. 5C). Injected dissociative agent combinations. The article overviews whether IP is the best option for euthanization based on evidence associated with welfare implications. (A) MSCs were labeled with DiR dye and given by three different ways. Nature medicine 5, 309313, doi: 10.1038/6529 (1999). C57BL/6 mice were brought from (68 weeks; SLACCAS, Shanghai, China), GFP transgenic mice ware brought from (The institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, China). Article Three days after MSCs transplatation, the mice were sacrificed for histological evaluation (H&E and phosphomolibidic acid-picrosirius red staining). 4A,B). [11] The effects of this study were the onset of flu-like symptoms, emesis, and abdominal pain. showed that incubation of human monoclonal IgG aggregates in plasma for 24 hrs resulted in alteration of the total number of aggregates, led to different aggregate size and changed their . One study attempted to diagnose hepatic hydrothorax with the use of injecting Sonazoid intraperitoneally. Here, we also compare the expression of FoxP3, which is frequently used to quantitate Treg cells. Gynecol Oncol 81, 7781, doi: 10.1006/gyno.2000.6108 (2001). [4] In 1964, a study delivered chemical agents such as acetic acid, bradykinin, and kaolin to mice intraperitoneally in order to study a "squirming" response. In this study, intraperitoneal (IP) injection was used to mimic the human administration route. In general, it is preferred when large amounts of blood replacement fluids are needed or when low blood pressure or other problems prevent the use of a suitable blood vessel for intravenous injection. PubMed Whole marrow cells are plated in the culture dish and non-adherent cells were removed during passage. Best way for mesenchymal stem cells transplantation for colitis. Interaperitoneal Administration of lpha-Tocopherol Loaded Nanoparticles Improves Ischemia-Reperfusion Injury in Rat Ovaries Torsion and Detorsion Model. Curr Opin Gastroenterol 30, 8496, doi: 10.1097/MOG.0000000000000031 (2014). Get the most important science stories of the day, free in your inbox. Language links are at the top of the page across from the title. MSCs has been found to directly differentiate into end-stage cells to augment bone damages and repair cartilage defects38,39. The overall therapeutic factors, MSCs migration and targeting as well as local immunomodulatory cytokines and FoxP3+ cells infiltration were analyzed. Article Am J Gastroenterol 105, 289297, doi: 10.1038/ajg.2009.579 (2010). The AI groups exhibited 9.5% and IV group showed 6.7% FoxP3+ cells, respectively (Fig. It was concluded in a review article that utilizing IP injections to administer drugs to laboratory rodents in experimental studies is acceptable when being applied to proof-of-concept studies.[15]. TSG-6 might be a major anti-inflammatory mechanism of MSCs, since not only in colitis model, the therapeutic effect of TSG-6 remotely secreted by MSCs were also identified in many other disease model46,48,49,50. Peyrin-Biroulet, L., Loftus, E. V. Jr., Colombel, J. F. & Sandborn, W. J. In various preclinical models, saroglitazar has been shown to prevent & reverse symptoms of NASH. PLGA Nanoparticles for the Intraperitoneal Administration of CBD in the Treatment of Ovarian Cancer: In Vitro and In Ovo Assessment. Although widely used as a means of administering substances, particularly injectable anaesthetics, this is an inherently unreliable technique, since inadvertent injection of some material into the gut, abdominal fat and subcutaneous tissues is a relatively frequent . official website and that any information you provide is encrypted & Gratwohl, A. Acute colitis was induced in C57BL/6 male mice by feeding 5% DSS (molecular weight 40000Da; Sigma) dissolved water for 5 days, followed by five days of regular drinking water according to our previously published study63. Article Best way for mesenchymal stem cells transplantation for colitis. In 2018, a patient with stage IV ovarian cancer and peritoneal metastases was injected intraperitoneally with 12g of mixed cannabinoid before later being hospitalized. Quantification of collagen fiber was assessed using Image Pro Plus software (version 6.0). With the computer-assisted software, we calculated the density of collagen fibers (%) of all groups. They are one of the few ways drugs can be administered through injection, and have uses in research involving animals, drug administration to treat ovarian cancers, and much more. Mesenchymal Stem Cells Reduce Colitis in Mice via Release of TSG6, Independently of Their Localization to the Intestine. Wang Min, Liang Cong and Hu Hao contributed equally to this work. The provided examples show a variety of uses for intraperitoneal injections in animals for in vitro studies. In consistent with Scaldaferris work, the increased TSG-6 after MSCs transplantation was also identified. 4F,G). Skin application of non-rodents (miniature pigs) Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Google Scholar. Bull Emerg Trauma. . (C) Percentage of body weight changes over time. After 3 passages, spindle-shaped cell colonies gradually predominate in the cultures. To determined cytokine in colon mucosa, protein extracts were isolated by homogenization of colonic segments (50mg tissue/mL) in 50mmol/L Tris-HCl, pH 7.4, with 0.5mmol/L dithiothreitol and 10 g/mL of a cocktail of proteinase inhibitors (Sigma). All reactions were performed in triplicated. While this route is an easy to master, quick, suitable for chronic treatments and with low impact of stress on laboratory rodents, there is a common concern that it may not be an acceptable route for drug administration in experimental studies. Pull back on the plunger to ensure negative pressure prior to injecting. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Hepatic and renal . These findings may benefit clinic practice. In that same year, a study injected egg whites intraperitoneally into rats to study changes in "droplet" fractions in kidney cells. Once the animal is properly restrained (as described above for SC injections) the injection site is . Levy, O. et al. We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are "retired" from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. Near-infrared imaging and quantification of MSCs transplants. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. This is really an interesting finding, however exact mechanisms are still unknown. Here, we combined the iDISCO + method and Fos immunostaining to confirm that the middle part of the right-side, but not the left-side, insular cortex in adult male mice is activated by intraperitoneal injection of lithium chloride. This study compared intraperitoneal injections, intravenous injections, and anal injections. DiR-labeled cells were injected into DSS mice by three different ways. Lu, Z., Wang, J., Wientjes, M. G. & Au, J. L. Intraperitoneal therapy for peritoneal cancer. Department of Digestive Diseases, State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xian, 710032, China, Min Wang,Cong Liang,Hao Hu,Lin Zhou,Bing Xu,Xin Wang,Ying Han,Yongzhan Nie,Jie Liang&Kaichun Wu, Department of Gastroenterology, Xian Childrens Hospital, 710006, China, Department of Respiratory and Gastroenterology, Second Peoples Hospital, Xian, 710005, China, Department of Gastroenterology, PLA No.5 Hospital, Yinchuan, 750004, China, You can also search for this author in The MSCs may exert their therapeutic effects on mainly three following aspects: firstly, to differentiate and replace the damage tissue; secondly, to secrete soluble immunomodulatory bioactive molecules and establish a regenerative milieu; thirdly, cell-to-cell contact and interaction with immune cells. The following approaches are novel, and require further testing in humans before being accepted as potential treatment options: After intraperitoneal injection of macrophages labeled with [3 H]cholesterol, the tracer can be detected in the plasma, liver, . In addition, MSCs showed inhibitory effects on proliferation of memory T-cells by direct cell contact52. Filipe et al. PubMed Fluorescent intensity was quantified and processed using the Living Image Software (Version 4.2; Caliper Life Science). These findings could be advanced by studying how the route of injection affects the organs in the peritoneal cavity. The delivery of OK-432 occurred a total of four times in a span of one week. Histological evaluation was completed in a double-blind fashion by two independent pathologist.
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