Experimental models of high-risk bowel anastomosis in rats: A systematic review

Table 1 Ischaemia models of high-risk anastomosis

Ref.	Year	Sample size	Intervention	Test	Sampling day
Uzun et al[20]	2008	56	Sildenafil citrate	NOx, thiobarbituric acid reactive substances, glutathione	3/7
Karliczek et al[21]	2009	34	Visible light spectrometry evaluation	BPR in situ, tensile strength	3/7
Coneely et al[22]	2010	50	Ketotifen	BPR ex situ, HP, IL-6, VEGF	4
Karataş et al[23]	2010	24	Amelogenin	BPR ex situ, HP	4
Kaya et al[24]	2010	48	Tadalafil	BPR ex situ, HP, histology (as per Ehrlich et al[25])	4
Adas et al[26]	2011	40	Bm-MSCs 1 × 106	BPR in situ, HP	4/7
Karatepe et al[27]	2011	40	Adrenomedulin	BPR ex situ, HP, spectrophotometry, MDA, NOx, TNF-a, IL-6, VEGF, histology	3/7
Kennelly et al[28]	2011	30	Electrical field stimulation	BPR ex situ, HP, IL-6, VEGF	4
Sümer et al[29]	2011	30	Pentoxifylline and vinpocetine	BPR in situ, HP, histology (as per García et al[30])	5
Yoo et al[31]	2012	60	AdMSC 1 × 106	BPR ex situ, weight loss, macroscopic (adhesions as per van der Ham and Kort[32], strictures, ulcers), histology (as per Phillips et al[33]), wound infection, ileus, mortality	7
Wu et al[34]	2013	24	Triptolide	Histology, calprotectin, MPO, INF-g, IL-4, IL-17, TGF-b	56
Portilla-de Buen et al[35]	2014	180	Fibrin glue	BPR ex situ, macroscopic, microscopic, HP	5
Boersema et al[36]	2016	40	Hyperbaric oxygen	Macroscopic (as per Zühlke et al[37]), histology (as per Phillips et al[33]), serum creatinine	3/7
Ruiz-Luque et al[38]	2019	93	Alprostadil	BPR in situ, macroscopic (as per Knightly et al[39]), histology (as per García et al[30])	8
Kayapinar et al[40]	2021	60	CORM-2	BPR ex situ, HP, glutathione, MDA, histology (as per Ehrlich et al[25])	3/7

BmMSC: Bone marrow derived mesenchymal stem cells; AdMSC: Adipose tissue derived mesenchymal stem cells; CORM-2: Carbon monoxide releasing molecule-2; NOx: Nitric oxide; BPR: Bursting pressure; HP: Hydroxyproline; IL: Interleukin; VEGF: Vascular endothelial growth factor; MDA: Malondialdehyde; TNF-a: Tumor necrosis factor–alpha; MPO: Myeloperoxidase; INF-g: Interferon-gamma; TGF-b: Tumor growth factor-beta.

Table 2 Colitis models of high-risk anastomosis

Ref.	Year	Colitis method	Sample size	Intervention	Test	Sampling day
Kirkil et al[41]	2008	Intra-jejunal injection of iodoacetamide	28	Endothelin receptor blockade by bosentan	BPR in situ, macroscopic (Mannheim index[42]), HP, histology (as per Mei et al[43])	4
Rijcken et al[44]	2010	7 d DSS 5%	Not mentioned	rhIGF-1	BPR in situ, microscopic (as per Phillips et al[33], Ki-67), HP, MPO	1/3/7
Myrelid et al[45]	2015	5 d DSS 3%	140	IP prednisolone, AZA, infliximab	BPR ex situ, bowel WT/length, histology, zymography	3
Alvarenga et al[46]	2019	2,4,6-TNBS	66	AdMSC 2 × 106	Histology, IL-10, IL-17, IFN-g, TGF-b, TNF-a, MMP-2, MMP-9	7
Reischl et al[47]	2021	ANXA-1 k/o mice and 7 d DSS 2%-3%-5%	Not mentioned	Ac2-26-nanoparticles	Fluorescence imaging of MMPs, histology (as per Phillips et al[33]), whole transcriptome RNA sequencing and analysis	3/7
Weber et al[48]	2023	7 d DSS 2%	84	Prednisolone	BPR in situ, macroscopic (adhesions scoring), histology (as per Philips et al[33])	3/7
Ntampakis et al[49]	2023	7 d DSS 5%	24	AdMSC 5 × 106	BPR ex situ, macroscopic (as per Bosmans et al[50]), HP, IL-6, TNF-a, VEGF	7

DSS: Dextran sodium sulphate; TNBS: 2,4,6-trinitrobenzene sulfonic acid; rhIGF-1: Recombinant human insulin-like growth factor-1; IP: Intra-peritoneal; AZA: Azathioprine; AdMSC: Adipose tissue derived mesenchymal stem cells; BPR: Bursting pressure; HP: Hydroxyproline; IL: Interleukin; VEGF: Vascular endothelial growth factor; TNF-a: Tumor necrosis factor-alpha; MPO: Myeloperoxidase; INF-g: Interferon-gamma; TGF-b: Tumor Growth Factor–beta; MMP: Metalloproteases.

Table 3 Malnutrition models of high-risk anastomosis

Ref.	Year	Colitis method	Sample size	Intervention	Test	Sampling day
McCauley et al[51]	1991	3,5% agar diet for 7 d	30	BCAA	Body WT, BPR ex situ, tensile strength, protein content, HP	-
Karahasanoglu et al[52]	1998	Low-protein diet for 10 d	40	Growth hormone	Body WT, BPR in situ, hydroxyproline	4
Salman et al[53]	2008	15 d	72	Cholerella sp. microalgae	Body WT, macroscopic (adhesions as per Ham et al[32]), BPR in situ, HP, histology (as per de Roy van Zuidewijn et al[54]), albumin, prealbumin, transferrin	3/5/7/9/11/13/15
Gonçalves et al[55]	2009	50% food restriction for 21 d	80	Pre-op nutrition	Tensile strength, histology	5
Gündoğdu et al[56]	2015	50% food restriction for 26 d	18	Pre-op nutrition	Body WT, BPR in situ, HP	4
Vizzotto Junior et al[57]	2015	Paired feeding	160	Omega-3	Body WT, tensile strength, histology	5
Danielski et al[58]	2016	50% food restriction for 26 d	45	Vitamin C	Body WT, macroscopic (as per Knightly et al[39]), histology, HP, MPO, TNF-a, nitrite/nitrate, oxidative damage	7

WT: Weight; BPR: Bursting pressure; HP: Hydroxyproline; TNF-a: Tumor necrosis factor–alpha; MPO: Myeloperoxidase; BCAA: Branch chained amino acids.

Table 4 Obstruction models of high-risk anastomosis

Ref.	Year	Obstruction method	Sample size	Intervention	Test	Sampling day
Törnqvist et al[60]	1990	Silicone ring 6.5 mm	54	Diverting colostomy	Tensile strength, weight, HP	2/7
Aguilar-Nascimento et al[61]	1997	Silk ligature	108	Nutritional solutions lavage of the colon	Macroscopic, histology	3/6
Erbil et al[62]	2000	Silk ligature	144	Nutritional solutions lavage of the colon	BPR ex situ, HP, macroscopic	3/6
Cağlikülekçi et al[63]	2002	Common bile duct ligation	40	rGH	BPR ex situ, macroscopic, HP, macroscopic, histology (as per Greenhalgh et al[64])	7
Lelyanov et al[65]	2004	Silk ligature	60	Sodium hypochlorite and ozone therapy	BPR ex situ, survival, macroscopic, histology	1/3/6/9/12
Krarup et al[59]	2017	Laparoscopic clip application	32	MMP inhibition	Body WT, HP, BPR in situ	3

HP: Hydroxyproline; WT: Weight; BPR: Bursting pressure; MMP: Metalloproteases; rGH: Recombinant growth hormone.

Table 5 Peritonitis models of high-risk anastomosis

Ref.	Year	Peritonitis method	Sample size	Intervention	Test	Sampling day
Vaneerdeweg et al[66]	2000	Gelatin capsule with faeces and barium sulphate	40	Gentamicin Sponges	BPR in situ, mortality, weight loss	4
Reijnen et al[67]	2002	Caecal ligation/perforation	198	Hyaluronan-based agents	tPA activity	1/3/7
Aydin et al[68]	2006	Caecal ligation/perforation	24	Laparostomy with Bogota bag	BPR in situ, HP, adhesions (as per Zühlke et al[37])	5
Li et al[69]	2006	Enterotomy	360	Fibrin glue and growth hormone	BPR in situ, HP, tensile strength, histology	1/3/5
Buyne et al[70]	2009	Faecal inoculation	148	Recombinant tPA	BPR in situ, tensile strength, macroscopic, HP	3/7
Kayaoglu et al[71]	2009	Caecal ligation/perforation	80	N-butyl-2-cyanoacrylate	BPR ex situ, macroscopic (as per Knightly et al[39]), histology	3/7
Pantelis et al[72]	2010	Caecal ligation/perforation or incomplete anastomosis	206	Collagen matrix coagulation factors I and IIa (Tachosil)	BPR ex situ, histology (as per Biert et al[73], Verhofstad et al[74], Attard et al[75]), collagen type I-II, HP	2/5/14
Rocha et al[76]	2010	Caecal ligation/perforation or incomplete anastomosis	45	Hyperbaric oxygen therapy	Total energy rupture test (tensile strength)	4
Silva et al[77]	2012	Caecal ligation/perforation or incomplete anastomosis	40	Bromopride	Macroscopic (Nair et al[78]), tensile strength (Versa test), histology, quantitative collagen analysis, HP	3/7
Holmer et al[79]	2014	Faecal inoculation	72	Collagen fleece coating	BPR in situ, histology, collagen I, III, VEGF, MMP-13	1/3/7
Camargo et al[80]	2013	Faecal inoculation	40	Peritoneal lavage with bupivacaine	Tensile strength, survival	5
Arikanoglu et al[81]	2013	Colon injury	21	Antibacterial suture	BPR in situ, HP, histology	10
Donmez et al[82]	2013	Colon injury	40	Glutamine and GH	BPR ex situ, HP	5
Senol et al[83]	2013	E. Coli inoculation	40	Fibrin glue	BPR ex situ, histology (as per Ehrlich-Hunt[25]), HP	10
Silva et al[84]	2014	Caecal ligation/perforation	80	Bromopride	MMP-1a, MMP-8, MMP-13, IL-1b, IL-6, IL-10, TNF-a, IFN-g	3/7
Erginel et al[85]	2014	Caecal ligation/perforation	40	IP O3	BPR ex situ, histology (as per Verhofstadt et al[74] and Philips et al[33]), HP	7
Pommergaard et al[86]	2014	Incomplete anastomosis	80	Tachosil coating	Tensile strength, clinical assessment	7
Ercan et al[87]	2015	Caecal ligation/perforation	40	IP L-Carnitine	BPR ex situ, histology (as per Ehrlich- Hunt[25]), HP	5
Cakir et al[88]	2015	Incomplete anastomosis	64	Sildenafil	BPR ex situ, histology (as per Phillips et al[33]), HP, MDA, GSH	3/7
Suárez-Grau et al[89]	2016	Incomplete anastomosis	56	Fibrinogen - thrombin collagen patch	Histology (as per Biert scheme[73]), macroscopic (adhesions), survival	15/30
Sozutek et al[90]	2016	Caecal ligation/perforation	50	PRP	BPR in situ, Body WT, HP, histology (as per Verhofstadt et al[74])	7
Ersoy et al[91]	2016	Caecal ligation/perforation	60	Melatonin	BPR ex situ, HP, histology, IL-6, IL-10, INF-γ, CRP	7
Çakır et al[92]	2016	Caecal ligation/perforation	18	IP O3	BPR ex situ, TNF-a, IL-1β, MDA, MPO, histology	22
Sukho et al[93]	2018	Incomplete anastomosis	60	AdMSC	BPR in situ, macroscopic (as per Verco et al[94] and Zühlke et al[37]), histology	3/7
Lorenzi et al[95]	2017	Caecal ligation/perforation	40	Omiganan	BPR in situ, histology (as per García et al[30]), HP	7
Yıldırım et al[96]	2021	Caecal puncture	21	Growth factor collagen (FGF-C), abx collagen (AB-C)	BPR ex situ, HP, macroscopic (as per Bosmans et al[50]), histology (as per Ehrlich et al[25])	7
Nakamura et al[97]	2021	Incomplete anastomosis	60	HSMM	BPR ex situ, macroscopic (as per Ham et al[32]), histology	3/5/7/14/28
Aksu et al[98]	2021	Colon injury	21	Chlorhexidine gluconate and metronidazole-soaked sponges	BPR in situ, hydroxyproline, histology	10
Yilmaz et al[99]	2021	Caecal ligation/perforation	32	Polyurethane membrane	BPR ex situ, HP, NOx, IL-6, TNF-a, tPA, macroscopic (as per Mazuji et al[100]), histology	5

BPR: Bursting pressure; WT: Weight; tPA: Tissue plasminogen activator; HP: Hydroxyproline; VEGF: Vascular endothelial growth factor; MMP: Metalloproteases; IL: Interleukin; MDA: MDA: Malondialdehyde; GH: Growth hormone; TNF-a: Tumor necrosis factor-alpha; IFN-g: Interferon-gamma; IP: Intra-peritoneal; GSH: Glutathione; MPO: Myeloperoxidase; AdMSC: Adipose tissue derived mesenchymal stem cells; HSMM: Human skeletal muscle myoblast; NOx: Nitric oxide.

Table 6 Radiation models of high-risk anastomosis

Study	Year	Radiation dose	Sample size	Intervention	Test	Sampling day
Liu et al[101]	2001	10 Gy	74	Lactobacillus plantarum 299v	Body weight, WBC, mucosal MPO, HP, nucleotide, DNA and RNA content, colonic bacterial microflora, bacterial translocation, histology	4/7/11
Kerem et al[102]	2006	500 cGy	84	Soluble Fiber	Macroscopic (adhesions as per van der Ham and Kort[32]), BPR in situ, HP, histology (as per de Roy van Zuidewijn et al[54]), MMP-2 activity	3/7
Ozdemir et al[103]	2013	800 rad	30	Amifostine	BPR ex situ, HP, histology	5
Seker et al[104]	2014	485 cGy	60	Pycnogenol	BPR ex situ, HP, MDA, histology (as per Houdart et al[105])	3/7
Simões Neto et al[106]	2013	660 cGy	30	Fraction electron beam	BPR (not specified), histology	7
Van de Putte et al[107]	2017	27Gy	48	AdMSC	18F-FDG-PET/CT, colonoscopy, histology	32
Taşdöven et al[108]	2019	6Gy	48	Ozon PR	BPR in situ, histology (as per Houdart et al[105]), HP, MDA, MPO	3/7
Yilmaz et al[109]	2022	20Gy	32	Ozon PR	BPR in situ, macroscopic (as per Knightly et al[39]), HP, MPO, histology (as per de Roy van Zuidewijn et al[54])	5

AdMSC: Adipose tissue derived mesenchymal stem cells; PR: Per rectum; MPO: Myeloperoxidase; HP: Hydroxyproline; MMP: Metalloproteases; BPR: Bursting pressure; MDA: Malondialdehyde.

Table 7 Ischaemia/reperfusion models of high-risk anastomosis

Ref.	Year	I/R method	Sample size	Intervention	Test	Sampling day
Terzi et al[110]	2001	SMA clampling 30 min	65	Allopurinol	BPR in situ, macroscopic (adhesions as per Knightly et al[39]), histology (as per de Roy van Zuidewijn et al[54])	3/7
Tireli et al[111]	2003	SMA clampling 30 min	20	Pentoxifiline	BPR ex situ, HP	7
Miranda et al[112]	2010	SMA clamping 45 min	45	Methylene blue	BPR ex situ, macroscopic, histology	7
Celik et al[113]	2013	SMA clamping 45 min	24	Modelukast	BPR ex situ, HP, MPO, MDA, caspase-3 activity, catalase, NOx, glutathione, SOD, TNF-a, IL-6, ALT, AST	5
Akarsu et al[114]	2017	SMA clamping 10 min	40	Simvastatin	BPR ex situ, HP	8
Özkan et al[115]	2018	SMA clamping 30 min	30	Melatonin	BPR ex situ, HP, histology (as per Nursal et al[116]), SOD, glutathione	7
Özçay et al[117]	2018	SMA clamping 45 min	40	GH	Macroscopic (as per Galili et al[118]), BPR ex situ, histology (as per Greenhalgh et al[64])	7
Sayin et al[119]	2020	SMA clamping 45 min	40	IP montelukast	BPR ex situ, macroscopic score (as per Knightly et al[39]), HP, histology (fibrosis)	7
Eryilmaz et al[120]	2020	SMA clamping 45 min	30	Hydrogen rich saline	BPR in situ, histology (as per Park et al[121] and Chiu et al[122]), TNF-a, IL-6, MDA, MPO	5
Akıncı et al[123]	2022	SMA clamping 30 min	36	Genistein	BPR ex situ, HP, SOD, glutathione, histology (as per Piroglu et al[124])	5

SMA: Superior mesenteric artery; GH: Growth hormone; IP: Intra-peritoneal; SOD: Superoxide dismutase; BPR: Bursting pressure; HP: Hydroxyproline; MPO: Myeloperoxidase; MDA: Malondialdehyde; IL: Interleukin; TNF-a: Tumor necrosis factor-alpha; I/R method: Ischaemia/reperfusion method.

Table 8 Chemotherapy models of high-risk anastomosis

Ref.	Year	Chemo agent	Sample size	Intervention	Test	Sampling day
Nayci et al[125]	2003	IP 5-FU	40	Electromagnetic field	Tensile strength, HP	7
Cetinkaya et al[126]	2005	IP mitomycin-C	81	GM-CSF	BPR ex situ, HP, histology (as per Ehrlich et al[25])	3
Kanellos et al[127]	2006	IP 5-FU and LEV	60	Fibrin glue	BPR ex situ, HP, macroscopic (adhesions as per van der Ham and Kort[32]), histology (as per Phillips et al[33])	8
Yildiz et al[128]	2013	5-FU and 20 Gy	60	HBOT	BPR ex situ, Weight, HP, histology (Fibrosis)	5
Arapoglou et al[129]	2017	Irinotecan	40	Iloprost	BPR ex situ, macroscopic (as per van der Ham and Kort[32]), histology (as per Phillips et al[33]), HP	8
Akyuz et al[130]	2018	5-FU IV	32	Melatonin	BPR ex situ, HP, histology, TNF-a, IL-1β	7
Ocak et al[131]	2019	HIPEC with CIS	30	PRP	BPR ex situ, HP, histology (as per Verhofstad et al[74])	7
Gorur et al[132]	2020	IP 5-FU	40	PRP	Body weight, BPR in situ, HP, histology (as per Verhofstad et al[74])	7
Buk et al[133]	2020	IP OX	30	PRP	BPR ex situ, histology (as per Verhofstad et al[74]), HP	7

IP: Intra-peritoneal; 5-FU: 5-Fluorouracil; LEV: Leucovorin; HIPEC: Hyperthermic intra-peritoneal chemotherapy; CIS: Cis-platina; OX: Oxaliplatin; GM-CSF: Granulocyte–macrophage colony stimulation factors; HBOT: Hyperbaric oxygen treatment; PRP: Platelet rich plasma; BPR: Bursting pressure; HP: Hydroxyproline; IL: Interleukin; TNF-a: Tumor necrosis factor-alpha.

Table 9 Immunosuppression models of high-risk anastomosis

Ref.	Year	Immunosuppression method	Sample size	Intervention	Test	Sampling day
Dinc et al[134]	2002	Methylprednizolone	80	GM-CSF	BPR ex situ, HP, histology (as per Ehrlich et al[25])	3
Colak et al[135]	2003	Dexamethasone	24	Trapidil	BPR ex situ, HP, histology (as per Ehrlich et al[25]), NOx, MDA	7
Sakallioglu et al[136]	2004	Dexamethasone	60	eGF	BPR ex situ, bursting site, HP, histology	7
Inglin et al[137]	2008	MMF	63	IGF-I	BPR ex situ, histology, Ki-67	2/4/6
Netta et al[138]	2014	Methylprednizolone	50	SCFA	BPR ex situ, CRP, IL-6, TNF-a	4
Karakaya et al[139]	2021	Everolimus	60	AdMSC	Macroscopic (as per Houston and Rotstein[140]), BPR ex situ, HP, histology	4/7

MMF: Mycophenolate mofetil; GM-CSF: Granulocyte-macrophage colony stimulation factors; eGF: Epidermal growth factor; IGF-I: Insulin-like growth factor; SCFA: Short chain fatty acids; AdMSC: Adipose tissue derived mesenchymal stem cells; BPR: Bursting pressure; HP: Hydroxyproline; NOx: Nitric oxide; MDA: Malondialdehyde; IL: Interleukin; TNF-a: Tumor necrosis factor-alpha.

Table 10 Macroscopic assessment of the anastomosis

Macroscopic assessment	Wound healing
van der Ham and Kort[32] score	Adhesions
Zühlke et al[37] score for adhesions	Adhesions
Mannheim index[42]	Peritonitis presence and severity
Knightly et al[39] score for adhesions	Adhesions
Bosmans et al[50] score	Anastomotic complication score
Nair et al[78] score	Adhesions
Verco et al[94] score	Abscess formation
Mazuji et al[100] score	Adhesions
Galili et al[118] score	Adhesions
Houston and Rotstein[140] score	Adhesions

Table 11 Histologic assessment of the anastomosis

Ref.	Histologic assessment
Ehrlich et al[25]	Erythrocytes, polymorphonucleated cells, mononuclear cells, fibroblasts, collagen fibers, fibrin
Houdart et al[105] and Hutschenreiter et al[144] as modified by García et al[30]	Mucosal anastomotic re-epithelialization, neovascularization, fibroblasts, fibrosis, muscle layer destruction, neutrophil infiltration, lymphocyte infiltration, histiocyte infiltration, giant cell infiltration
Ehrlich et al[25] as modified by Phillips et al[33]	Inflammatory cell infiltration, blood vessel in growth, fibroblast ingrowth, collagen deposition
Houdart et al[105]	Granulocyte infiltration, mononuclear cell infiltration, fibroblastic proliferation, focal necrosis, exudate formation
Mucosal damage index by Mei et al[43]	0: Normal mucosa, no damage on mucosal surface; 1: Mild hyperemia and edema, no erosion or ulcer on mucosal surface; 2: Moderate hyperemia and edema with erosion on mucosal surface; 3: Severe hyperemia and edema with necrosis and ulcer on mucosal surface, the major ulcerative area < 1 cm; 4: Severe hyperemia and edema with necrosis and ulcer on mucosal surface, the major ulcerative area > 1 cm
de Roy van Zuidewijn et al[54]	Re-epithelialization, regeneration of muscularis propria, mucosal muscularis propria damage, necrosis, inflammatory exudate, granulation tissue, granulocytes, macrophages, fibroblasts, granulation tissue
Greenhalgh et al[64]	Epithelization, cellular infiltration, fibroblastic proliferation, collagen deposition, neovascularization
Biert et al[73]	Necrosis, polymorphonuclear cells, lymphocytes, macrophages, edema, epithelium, submucosal - muscular continuity, neovascularization, fibrosis
Attard et al[75]	Mucosal continuity, muscular continuity, re-epithelialization, granulation tissue, polymorphonuclear cells, lymphocytes, macrophages, fibroblasts
Verhofstad et al[74]	Necrosis, polymorphonuclear cells, lymphocytes, macrophages, edema, mucosal continuity, submucosal – muscular continuity
Nursal et al[116]	Fibroblast infiltration, capillary formation, re-epithelialization, granulocyte infiltration, mononuclear cell infiltration
Park et al[121] and Chiu et al[122]	Grade 1: Normal mucosa; grade 2: The subepithelial space at the tip of the villus; grade 3: Increase in subepithelial space; grade 4: Overlapping and spills of the floor of the villus; grade 5: Disintegration of the lamina propria; grade 6: Crypt layer injury; grade 7: Transmucosal infarction and grade 8: Transmural infarction
Piroglu et al[124]	Inflammatory cell infiltration/concentration, neovascularization, fibroblastic activity, collagen fibers
Miltschitzky et al[15]	Blood vessel ingrowth, fibroblasts, collagen formation, inflammatory cell infiltration, first layer in which continuity has been restored, number of healed layers, epithelium closed, crypt architecture restored, overall healing quality