TABLE 2.

Anti‐Adhesion Research

Function	Nano‐scale carrier	Drug/gene?	Membrane/solution	In‐vitro result	In‐vivo result	References
Fibroblasts proliferation; infection	Ag nanoparticles	N/A	Electrospun poly(l‐lactide) PLLA membrane	Less fibroblasts proliferation (Not related to adhesion pathology, can only prove no cell attachment for antibacterial property)	N/A (lack of evidence for proving anti‐adhesion property)	105
Fibroblasts attachment; infection; inflammatory response	Ag nanoparticles	Ibuprofen	Poly (ethylene glycol) (PEG)/Poly (caprolactone) (PCL) Shell Hyaluronic acid (HA) Core	Less cell attachment and good biocompatibility (not related to adhesion pathology, can only prove no cell attachment for antibacterial property).	Less inflammation and adhesion have been observed on core‐shell nanofibrous membranes directly as well as through histology (no inducing adhesion model and adhesion score to quantify the data).	106
Collagen Type I expression	Dextran glassy nanoparticles (DGNs)	bFGF	Electrospun PLLA membrane	Less multipotent C3H/10 T1/2 cell attachment with good biocompatibility	A blunt dissection for separating the tendons and peritendinous tissues for treated group compared to control with sharp dissection as well as quantifying the breaking force for all groups.	107
Collagen Type I and PCNA protein expression	PLGA Nanoparticles	Constructed an overexpressed bFGF+VEGFA genes with GFP in pEGFP‐N1 plasmid	PEI Polymer suspension	Low cytotoxicity on samples carried out with MTT cell viability test, and high transfection rate of the tenocytes cell culture determined the effectiveness of the gene delivery.	Adhesion score of white Leghorn chicken in‐vivo model significantly decreased with treatment and the tendon ultimate strength increased representing good healing results.	108
TGF‐β1	Polylactic‐co‐glycolic acid (PLGA) Nanoparticles	miRNA based RNA interference (RNAi) plasmid	Polyethyleneimine (PEI) polymer suspension	Low cytotoxicity on samples carried out with MTT cell viability test.	Adhesion score, real‐time PCR, western blot of chicken tendon repair model with nanosphere/plasmid effectively inhibit the expression of TGF‐β1 for over 70% till week 6.	109
Phosphorylation of ERK1/2 and SMAD2/3	N/A	Fresh amnions (include TGF‐β1, bFGF, VEGF, and PDGF)	PCL electrospun nanofibres	Higher cell viability and proliferation on tenocytes and fibroblasts showed a better proliferation activity compared to control, 7 days cell culture also showed ERK1/2 and SMAD2/3 protein expression higher than control.	Adhesion score macroscopic and microscopic decreased on PCL electrospun treated group compared to control and amnions group. Histological healing percent also showed the best on PCL electrospun group.	110
Down‐regulate proinflammatory gene and protein expression (Tgfb3 and Tgfbr2), up‐regulate inhibitory proteins Smad6 and Smad7, ghrelin induce blockage of TGF‐β signaling	N/A	Ghrelin	N/A	N/A	In‐vivo mice model showed that ghrelin inhibits the TGF‐β/Smads and p‐38 MAPK signaling pathways activation during the inflammatory response at the onset of injury before the granulation‐remodeling phase occurs, which significantly reduce the local inflammatory mediators and therefore prevent adhesion	111
Enhance fibrinolytic and enhance EGF‐HER1 signaling by regulating macrophage	N/A	Plasminogen activator inhibitor 1	Carboxymethylcellulose (CMC)	N/A	The results have showed that the incidence of adhesions have been reduced but not eliminated in gauze induced adhesion rat model. The pharmacologic inhibition of PAI‐1 can prevent adhesion without the fear of bleeding, anastomotic disruption, and wound dehiscence.	112
PAI‐1 and tPA levels	N/A	tissue‐type plasminogen activator (tPA)	Poly(ε‐caprolactone)‐poly(ethylene glycol)‐poly(ε‐caprolactone) (PCEC)	N/A (Only drug release efficiency carried out in‐vitro experiment for a 14‐days slow release)	Adhesion score and frequency showed lower score for tPA‐hydrogel treated group, H&E staining as well as tPA and PAI‐1 level carried out with tPA‐hydrogel system	113
Fibrin deposition; angiogensis; macrophage infiltration	Peritoneal cell sheet (Include mesothelial cells and fibroblasts)	N/A	N/A	N/A	Peritoneal cell sheet transplantation prevents tissue adhesion, fibrin deposition, angiogenesis, lymphomagenesis, and macrophage infiltration in a rat cecal cauterization adhesion model.	114
Angiogenesis inhibitor, COX‐2 inhibitors drugs	N/A	Celecoxib, rofecoxib	Methylcellulose, silicone patch	N/A	Rats treated with selective and nonselective COX‐2 inhibitors had significantly fewer adhesions than control animals. Adhesions from mice treated with celecoxib had reduced microvessel density compared with rofecoxib, the nonselective COX inhibitors, and control animals.	205 115
Promote mesothelial cell proliferation; enhance fibrinolytic activity	N/A	Keratinocyte growth factor (KGF)	Sodium hyaluronate (HA) gel	N/A	The combination of KGF and HA can inhibit the severity of the fibrous changes in the adhesion induced rat model	116
Mesothelial cells Actin cytoskeleton (calcium channel); Anti‐adhesion	N/A	Small molecular calcium channel blocker (Bepridil, CK‐666, Rhosin, and Golgicide)	2% Cellulose	Unstressed cytoskeleton effect of GFP labeled mesothelial cells in situ induced in‐vitro assay mesothelial cells with calcium channel blocker drug treatment.	Adhesion score of rats with different dosage of the calcium channel blocker treated and tested 27 targets of signaling pathway with single‐cell transcriptomics analyses to prove the adhesion related gene expression.	15
T cells in TLR4/MyD88/NF‐κB signaling pathway	Polylactic acid (PLA) nanoparticles	ligustrazine	Potassium dihydrogen phosphate/ sodium hydroxide solution suspension	N/A (Only drug release efficiency carried out in‐vitro experiment)	Adhesion score, Masson trichrome (MT) staining, ELISA, western blotting, Immunohistochemistry and PCR shows significantly lower adhesion formation due to inactivating the TLR4/MyD88/NF‐κB pathway as well as regulating the downstream cytokine expression.	117
Anti‐adhesion, immune cell infiltration	Mesoporous silica nanoparticles	Ibuprofen	Electrospun PLLA composite	N/A (Only drug release efficiency carried out in‐vitro experiment)	Adhesion score and H&E staining showed an improvement for anti‐adhesion and anti‐inflammatory results of treated group with drug‐loaded nanoparticles compared to control.	78
Anti‐adhesion	PLGA Nanoparticles	N/A	Aldehyde‐ and hydrazide‐modified hyaluronic acids (HA)	Low cytotoxicity on murine mesothelial cells	Adhesion score of rats and rabbits model showed no adhesion on over 60% of animals treated with this gel system compared to over 50% of animals on control group with severe adhesions.	118
Anti‐adhesion, reduce formation of intrauterine adhesion	N/A	N/A	Crosslinked hyaluronan gel	N/A	60 patients were divided into two groups: Group 1 received curettage plus crosslinked hyaluronan gel (intervention group), and Group 2 received curettage alone (control group), Results showed hyaluronan gel reduce the formation of intrauterine adhesions in women after curettage for retained placental tissue after medically induced or spontaneous pregnancy loss in the second trimester	119
Anticoagulation	N/A	Heparin	Carboxymethylcellulose (CMC)	N/A	Adhesion score have significantly decreased with tiny doses of heparin, in combination with CMC 4% gel in two different animal models. (Two different types of animal models: Avascular knot model and Cecal abrasion model)	120
Antibacterial, hemostatic, anti‐inflammatory and biocompatibility	N/A	N/A	Nanochitosan membrane barrier	Higher adherence and biocompatibility (over 90%) on the material with a mouse fibroblasts L929 cell culture.	Rats' open abdominal cavity model proved nanochitosan membrane can reduce the invasion of inflammatory cells into the wound and inhibits the synthesis of collagen to prevent postoperative adhesions	121
Intracellular glutathione levels; Anti‐inflammatory; antioxidant	N‐acetylcysteine (NAC) nanoparticles	N/A	N/A	N/A	Adhesion score and C‐Reactive protein concentration showed a better result of lower doses of Nano‐NAC (50 and 75 mg/kg) compared to higher dose and control.	122
Anti‐inflammatory and anti‐oxidant; anti‐proliferation of fibroblast	N/A	Phlorotannin	Poly (ε‐caprolactone) film	Less fibroblasts proliferation and inhibit nitric oxide production (Not related to adhesion pathology, can only prove no cell attachment for antibacterial property)	N/A	123
Anti‐inflammatory, antioxidant, and antifibrotic effects	N/A	Pirfenidone	Carboxymethylcellulose (CMC)	N/A	Rat model revealed that pirfenidone has remarkable protective effects against postoperative intraabdominal adhesions and inflammation with a decreased mRNA expression levels and increased MMP‐9 concentration detected in peritoneal tissue.	124
Anti‐inflammatory	N/A	N/A	Human amniotic membrane	N/A	There were significantly fewer adhesions in the amniotic membrane group (2) versus hyaluronic acid (3) group (p = 0.01).	125
Anti‐inflammation and anti‐oxidation effects	N/A	20(S)‐ginsenoside Rg3	20(S)‐ginsenoside Rg3‐loaded methoxy poly (ethylene glycol)‐block‐poly(L‐lactide‐co‐glycolide) (mPEG‐b‐PLGA) electrospun membrane (PEM/Rg3)	N/A	PEM/Rg3 membranes showed a significantly reduce of the peritoneal adhesion in rats model.	126
Anti‐inflammatory, promote healing, reduce fibrous adhesion	Nanomicelles	Lipophilic gold nanorods and curcumin	Lipophilic gold nanorods stabilized with the surfactant agent hexadecyltrimethylammonium bromide	N/A	The rat model showed controlled release of curcumin from these nanomicelles can effectively reduce adhesion formation while promoting tendon healing	127
Anti‐inflammatory; antioxidant; RhoA/ROCK signaling pathway	N/A	Rho GTPases	Sodium aescinate (AESS)	The cytotoxicity assay was used to decide the concentration of the AESS with cell proliferation inhibition condition.	AESS significantly reduces postoperative adhesion formation in a rat model; AESS increases the secretion and activity of tPA in peritoneal fluid and decreases FIB levels in plasma. AESS‐treated groups showed that the secretion, activity, and expression of tPA in rat peritoneum were notably increased.	128
Physical barrier for pericardial adhesion	PLA–PEG nanoparticles	N/A	HPMC‐C12	N/A	Adhesion score of rats and sheep model treated with a PNP hydrogel adhesion barrier exhibited formulation‐dependent results, solid‐like PNP hydrogel formulations (G′ > G′′) 1:5, 1:10 and 2:10 all formed physical adhesion barriers that significantly reduced the incidence and severity of adhesions when compared with the untreated control group.	129