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Review
. 2022 Feb 23;7(1):17.
doi: 10.1038/s41536-022-00211-0.

Animal studies for the evaluation of in situ tissue-engineered vascular grafts - a systematic review, evidence map, and meta-analysis

Suzanne E Koch #  1   2 , Bente J de Kort #  1   2 , Noud Holshuijsen  1   2 , Hannah F M Brouwer  1   2 , Dewy C van der Valk  1   2 , Patricia Y W Dankers  1   2 , Judith A K R van Luijk  3 , Carlijn R Hooijmans  3 , Rob B M de Vries  3 , Carlijn V C Bouten  1   2 , Anthal I P M Smits  4   5
Affiliations
Review

Animal studies for the evaluation of in situ tissue-engineered vascular grafts - a systematic review, evidence map, and meta-analysis

Suzanne E Koch et al. NPJ Regen Med. .

Abstract

Vascular in situ tissue engineering (TE) is an approach that uses bioresorbable grafts to induce endogenous regeneration of damaged blood vessels. The evaluation of newly developed in situ TE vascular grafts heavily relies on animal experiments. However, no standard for in vivo models or study design has been defined, hampering inter-study comparisons and translational efficiency. To provide input for formulating such standard, the goal of this study was to map all animal experiments for vascular in situ TE using off-the-shelf available, resorbable synthetic vascular grafts. A literature search (PubMed, Embase) yielded 15,896 studies, of which 182 studies met the inclusion criteria (n = 5,101 animals). The reports displayed a wide variety of study designs, animal models, and biomaterials. Meta-analysis on graft patency with subgroup analysis for species, age, sex, implantation site, and follow-up time demonstrated model-specific variations. This study identifies possibilities for improved design and reporting of animal experiments to increase translational value.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. PRISM flow chart of study selection process.
The systematic search in Pubmed and EMBASE yielded 15,896 unique publications. After title and abstract screening, articles were screened full text of which 1,182 articles were excluded based on the exclusion criteria. Data from 182 articles (see Supplementary Reference List) was extracted and because of incomplete reporting (e.g., animal number not reported) in 26 articles, 156 articles were included in meta-analysis. Abbreviations: TE tissue engineering.
Fig. 2
Fig. 2. Number of animals and publications on in situ TEVG.
a Number of studies and number of animals per species combined per decade. Size of the dot represents total number of animal used (total number of animals per publication, e.g., in situ TEVG and control grafts), location of the dot on y-axis represents total number of studies published per decade per species. b Number of publications on animal studies of in situ TEVG per publication year. Abbreviations: TEVG Tissue Engineered Vascular Graft.
Fig. 3
Fig. 3. Mapping of study characteristics included in the systematic review.
a Number of publications per species of all included studies. b Number of subgroups reporting health status of animals all included studies. Compromised animal models include; coagulation adjustments (e.g., platelet inhibitor treatment), Knock out (KO) models (e.g., Myeloid specific PDGF KO, CCR2 KO), metabolically challenged models (e.g., Diabetic animals), and immune compromised animals (e.g., SCID/beige, athymic). c Reported animal sex, and d animal age of all experimental groups and categorized per animal species according to cut-off values described in Table 1.
Fig. 4
Fig. 4. Mapping of study characteristics included in the systematic review.
a Follow-up time in days for all experimental groups categorized per species, black vertical line indicates average. b Follow-up time of all experimental groups and categorized per animal species according to cut-off values described in Table 1.
Fig. 5
Fig. 5. Mapping of study characteristics included in the systematic review.
a Graft diameter (in mm) per study per species. Numbers below species indicate n publications describing this characteristic/total publications. b Graft length (in mm) per species. c Graft length/diameter ratio per species. d Graft wall thickness (in µm) per species. e Implant site (arterial, venous) and small (<6 µm) and large (>6 µm) inner diameter. Abbreviations: NR Not Reported.
Fig. 6
Fig. 6. Mapping of materials used for in situ TE vascular grafts per species.
Relative size represents number of studies using the specific material type. Blended materials are separated by /, and different graft layers are separated by +. Abbreviations: PHEA a,b-poly(N-2-hydroxyethyl)-D,L-aspartamide, CE-Upy Chain extended-ureido-pyrimidinone, PTX Paclitaxel, PBF poly(2,3-butylene furmarate), PMEH poly(2-methacryloyloxyethyl phosphorylcholine-co-2-Ethylhexyl methacrylate), PUSN poly(ester urethane)urea with disulfide and amino group, PetU poly(ether)urethane, P(LA-co-GA) poly(lactid acid-co-glycolic acid), P(LLA-co-CL) poly(L-Lactic-co-caprolactone), P(BT-block-EG) poly(polybutylene terephthalate-co-polyether glycol), PA polyamide/nylon, PCL polycaprolactone, PCU polycarbonate urethane, PDMS polydimethylsiloxane, PDS polydioxanone, PDLA poly-D-L-lactic acid, PEU polyesterurethane, PEUU polyesterurethane urea, PEG polyethylene glycol, PGA polyglycolic acid, PGS polyglycerol sebacate, PLLA poly-l-lactic acid, PU polyurethane, PVA polyvinyl alcohol, SE synthetic elastin.
Fig. 7
Fig. 7. Mapping of reported read-outs for preclinical TEVG assessment and patency assessment methods.
a Number of studies reporting on read-outs; patency, cellularity, endothelialization, material degradation, collagen formation, elastin formation, calcification, and mechanical characterization. b Number of studies per patency assessment method; combination of both angiogram and ultrasound, angiogram, ultrasound, magnetic resonance imaging (MRI), macroscopic observation for pulsations distal to graft upon explantation, gross morphology upon explantation and histology, or not applicable (number of studies not reporting on patency).
Fig. 8
Fig. 8. Assessment of quality of study design and quality of reporting.
For all 182 included studies quality was assessed with 26 questions related to experimental set-up, study outcome design, animal information, procedure, and general outcome (see Supplementary Table 4 for the definition of separate answers per study).
Fig. 9
Fig. 9. Meta-Analysis and subgroup analyses.
a Subgroup analysis for species, b sex, c age, d implant site and diameter, and e follow-up time. Age and follow-time subcategorization are species-dependent; see Table 1 for cut-off values young vs adult (c) and short vs medium vs long (e) per species. Numbers in bar represent number of experimental groups. Black dotted line and gray shades representing grouped ER with 95% CI respectively. Red dotted line: overall ER patency. Significance *p < 0.05.
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