Systematic Reviews
Copyright ©©The Author(s) 2022.
World J Stem Cells. Jan 26, 2022; 14(1): 117-141
Published online Jan 26, 2022. doi: 10.4252/wjsc.v14.i1.117
Table 1 Kind of stem cells employed in published studies classified by their origin and type of transplant
Kind of stem cells employed
Bone marrow MSCs
ALLOG: 1AUT: 1; ALLO: 2AUT: 7; ALLOG: 4; XENOG: 2872
Table 2 Systems utilized to apply stem cells
SCs delivery system
Local injection
Systemic injection
Local + systemic injection
Cell sheets
Gelatin sponge
Stent + mesh
Table 3 Animal species employed in published preclinical studies
Type of animals
12 (9 colorectal, 3 gastric perforation)4 (small bowel and biliary anastomoses)1 (esophageal fistula)
Table 4 Overview and concise review of different published studies related to digestive anastomosis/perforations and stem cell therapy in animal models
Anast/perf model and repair
SC doses and type
SC treatment
Compared to
Effect measure
Follow up              
Principal results
Security concerns
Colon and colorectal anastomoses
Pascual et al[32]Rats (BDIX)40NoRight colon section. Interrupted end-to-end1.5 × 106 SYNG ASCs20 biosuturesConventional sutureSurgical evaluation (dehiscence, dilatation, obstruction, adherences). Bursting pressure; Histology4, 7, 14, 21 dLower adhesion index at 4 d (P = 0.025) and 7 d (P = 0.006). No differences in the other outcome measuresNo
Pascual et al[36]Rats (BDIX + SD)18NoIdentical to high risk: icodextrin. IdenticalSYNG ASCs6 biosutures + icodextrinConventional suture +/- icodextrinSurgical evaluation (dehiscence, adhesion). Bursting pressure4 dNo differences in dehiscence. Conventional sutures: icodextrin ↓ adhesion and MBP. Icodextrin: Biosuture ↑ MBP with equal adherencesNo
Adas et al[37]Rats (WI)40NoIschemic: Left colon section + 4 cm vessel ligation. Interrupted end-to-end.5 × 105 ALLOG BM-MSCs20 local injectionSaline solutionSurgical evaluation. Bursting pressure. Hydroxyproline. Histology. SC tracing4 and 7 dNo leakages, peritonitis, mortality. SCs ↑ MBP (2×) and hydroxyproline. Histology favourable for healing at both timelines. SC survive and proliferateNo
Yoo et al[38]Rats (SD)60NoIschemic: Left colon section + vessel ligation until > 50% flow reduction. End-to-end PLP. 1 × 106 ALLO ASCs30 local injection + fibrinogen & thrombinIschemic anastomosesClinical follow-up: Surgical evaluationABP. Histology7 dASCs: ↓ weight loss and earlier weight recovery; ↓ ileus, ulcers and strictures. ↑ MBP. Histology: SCs ↓ inflammation and ↑ collagen and microvascular density.No
Adas et al[39]Rats (WI)40NoIschemic: Left colon section + 4 cm vessel ligation. End-to-end interrupted1 × 106 ALLOG BM-MSCs20 systemic injectionSaline solutionSurgical evaluation. Bursting pressure. Hydroxyproline. Histology. SC tracing4 and 7 dNo leakages, peritonitis, mortality. SCs ↑ MBP (43%) at 4th but not 7th day. SCs ↑ SS hydroxyproline. Histology SS favourable for healing (4, 7d). SC Survive and proliferateNo
Sukho et al[40]Rats (WI)60YesPartial right colectomy. Insufficient end-to-end (5 stitches).XENOG human ASCs30 sheets wrapping anastomosisInsufficient anastomosisFollow-up: Macroscopic evaluation. ABP. Histology3 and 7 dASCs ↓ dehiscence (14% vs 71%) at 3 d, abscesses at 7 d and abdominal adhesions at 3 d. ABP ↑ 3 to 7 d, but NSS differences between groups. Labelled cells detected at both periods. Histol: SCs ↑ CD3+ and maintain CD163+ cells at 7 d.No
Van de Putte et al[43]Rats (SD)24NoIrradiatedColon section. Interrupted end-to-end5 × 106 IV and 2.5 × 106 local. ALLOG ASCs10 local injection + IV -7, 10, 20 dConventional anastomosis. Irradiation + anast + PBSPET. Colonoscopy. Histology4 wkPET: preop IV ASCs ↓ activity to non-irradiated level. No differences at 4 wk. Colonoscopy: ASCs ↓ necrotic tissue and fibrin and bleeding (??P). Histology: SS ASCs ↓ ulcerated area and ↑ number vessels. ↑ M2 macrophages (??P).0/3/3 deaths. No ASCs related
Alvarenga et al[44]Rats (WI)61YesTNBS colitis. Left colon section. Ent-to-end interrupted2 × 106 ALLOG ASCs15 instillation over anastomosisG1, TNBS colitis. G2, Laparotomy. G3, colitis + anast. G5, colitis + anast + CSFollow-up: Macroscopic. Histology, IHQ, RNA7 dASCs ↓ mortality to 0% compared to G3/G5 and local complications to 0%. ASCs: ↓ inflammation, tissue damage, myeloperoxidase activity, CD4+ and ED1+ macrophages, apoptosis; and ↑ epithelization (vs G5). ASCs: ↓ IFN-γ. TGFβ, IL-17, TNF-α, and MMPs are not ↑ (as in G5), NSS, and equal to G2/G3.No
Morgan et al[45]Rats (WI)48NoIschemic: Left colon resection + Vessel ligation. End-to-end interrupted. Air checked1 × 106 XENOG human ASCs16 ASCs Gelatin sponge wrappingAnastomosis. Anastomosis + gelatin sponge wrappingFollow-up: Macroscopic. MBP in situ. Histology, IF, rtPCR. SC tracing3 and 7 dNo mortality/complications. ASCs: ↓ AL and abscesses (3, 7 d); ↓ adhesions (3 d). No changes in MBP. ASCs ↑ collagen and microvascular density. Labelled cells in submucosa and muscularis. No SS differences in rtPCR.No
Small bowel anastomoses
Maruya et al[46]Pigs7Yes (anast)High risk: vessel ligation + local mitomycin C. 8/animal. Multilayer end-to-endAUT ASCs28 anastomoses wrapped with 3 ASCs sheetsAnastomosis without sheetsMBP, histology and hydroxyproline (5, 7d). mRNA (1, 7d)1, 5, 7 dASCs: MBP ↑ at 7 d, similar to normal healing. ASCs ↑ hydroxyproline at 7 d. ASCs ↑ submucosal collagen 7 d (??P). ASCs: ↑ FGF2, COL1A1 and COL3A1 day 1 and COL1A1 and COL3A1 day 7.No
Pan et al[47]Pigs16No5/animal. Section. Functional end-to-end (energy sealing device)0.5 × 106 ALLO ASCs8 × 5 anastomoses. Local injectionAnastomosis without ASCsFollow-up: Macroscopic. MBP. Histology, IHQ, IF, western, PCR arrays. SC tracing7, 14 dNSS in complications/leakage and MBP. ASCs: Reepithelialization and ↑ collagen at 7 d (??P). ASCs ↑ proliferation, and ↓ CDH1, SMAD3, STAT3, TGF-α, VEGFA. Labelled cells in mucosa.1 death in ASCs (ileus)
Digestive (gastric) perforations
Komiyama et al[48]Rats (WI)40NoGreater curvature incision. Block continuous suture1 × 107 AUT ASCs20 local injectionPBS local injectionHistology day 7 (n = 5), day 28 MBP, day 7 (n = 5) SC tracing7 and 28 dLabelled cells at 7, 28 d without differentiation. ASCs ↑ neovascularity and connective tissue at 7 d and ↓ connective tissue at 30 d. MBP ↑ 7 d with ASCs.No
Liu et al[49]Rats (SD)108No2 cm body incision. Interrupted suture5 × 106 AUT ASCs24 local injection. 24 topical in fibrin glue Sham operated. PBS injection. Topical fibrin glueMacroscopic. Histology. IHQ, IF, western. SC tracing3, 5, 7 dInjected ASCs ↓ severe adhesions (3, 5, 7 d), dehiscence (3 d), abscesses (7 d). 20% total healing at 7 d (vs 0%). ASCs ↑ MBP (5, 7 d). Injection the highest values (comparable to sham operated at 5 d). ASCs ↓ inflammation and ↑ granulation (5, 7 d, ??P), more with injections. Injected ASCs ↓ IL-6 (day 5, 7) and ↑ TGFβ1 (day 3, 5). Label+ cells submucosa/granulation, differentiation+.No
Tanaka et al[50]Rats (SD)30N5 mm incision. No sutureALLO myoblasts sheet15 sheet placed with shifterNo sutureMacroscopic (adhesion). Blood and ascites. Histology. SC tracing3, 5, 10, 20 dSheets ↓ adhesions in all periods. Histology: sheets regenerated mucosa and muscle; control connective tissue (??P). Myoblast in gastric wall. ↓ SS peritoneal fluid hyaluronic acid (??P) all periods.No
Oesophageal anastomotic leakage/fistula
Xue et al[51]Rabbits21NoTransection, incomplete anast, tube during 7 d.2 × 106 AUT MSCs12 MSCs in fibrin sealant in fistula9 fibrin sealantCervical MRI (5 wk). Macroscopic, histology, IF, cytokine at 8 wk. SC tracing5, 8 wkMRI: ↓ inflammatory reaction MSCs. Macroscopic: ↑ closure and ↓ infection MSCs. Histology/IF: MSCs survive & differentiate. Milder inflammation and less collagen (??P) with MSCs. MSCs: ↑ IL-10, MMP-9 and ↓ TNF-α, TGF-β.5/9 control, 3/12 MSCs died (NSS)
Biliary anastomoses leakage/stenosis
Zhang et al[52]Pigs9NoCBD transection. Running sutures4 × 106 AUT ASCs3/3 stent + mesh with ASCs. Topical ASCs3 plastic stent + vycril meshSerum BQ (0, 7, 30 d). Cholangiogram 30 d. Histology, IHQ and IF 30 d0, 7, 30 dNo clinical/laboratory suggesting cholestasis. No leaks/stenosis on cholangiogram (??P). Topical ASCs ↑ SS CD44, CD34 (MSCs) and CD31 (angiogenesis) and ↓ fibrosis and inflammation (??P).1 death (ASCs + mesh) – cholangitis
Hara et al[53]Pigs11NoHepatic conduct section. End-to-end running (post)/interrupted (ant)AUT ASCs6 ASCs sheets around anastomosis5 anastomosis without sheetsBlood (0, 7, 14 d). Macroscopic, histology at 14 d0, 7, 14 dNo leakages, abscesses, mortality, lab cholestasis. Macroscopic: CBD diameter higher in controls due to wall thickening. Histology: ↓ inflammation, collagen and ↑ small vessels with ASCs (??P)No