Abdominal aortic aneurysm (AAA) is the pathological dilation and weakening of the abdominal aorta wall. Inflammation, degradation of the extracellular matrix (ECM) and loss of smooth muscle cells and skewing of their function are pivotal in AAA pathology. We developed a recombinant collagen-based patch (RCP) to provide structural integrity and deliver Adipose tissue-Derived Stromal Cells (ASC) for repair. Patches supported adhesion and function as well as proliferation of ASC. ASC-loaded RCPs or bare patches, applied around the aorta after AAA induction in rats, both maintained structural integrity of the aortic wall at time of explant (2w). However, wall thinning, accompanied by loss of elastin fibers and loss of medial SMC, was only attenuated in ASC-loaded RCP-treated AAA rats. Interestingly, this coincided with migration of ASC into the media and a reduced influx of macrophages. We hypothesize that the medially-migrated ASC dampened or skewed the adverse innate immunity and thus suppressed SMC apoptosis, phenotypic skewing and elastin degradation. We conclude that the periadventitial delivery of ASC with RCP suppresses development and progression of AAA, which is has an expected future clinical benefit in combination with an appropriate early screening program of patients at risk for aneurysms. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2494-2506, 2018.

BackgroundStem cell therapy to improve cardiac function after myocardial infarction is hampered by poor cell retention, while it may also increase the risk of arrhythmias by providing an arrhythmogenic substrate. We previously showed that porcine adipose tissue-derived-stromal cells (pASC) induce conduction slowing through paracrine actions, whereas rat ASC (rASC) and human ASC (hASC) induce conduction slowing by direct coupling. We postulate that biomaterial microspheres mitigate the conduction slowing influence of pASC by interacting with paracrine signaling.AimTo investigate the modulation of ASC-loaded recombinant human collagen-based microspheres, on the electrophysiological behavior of neonatal rat ventricular myocytes (NRVM).MethodUnipolar extracellular electrograms, derived from microelectrode arrays (8x8 electrodes) containing NRVM, co-cultured with ASC or ASC loaded microspheres, were used to determine conduction velocity (CV) and conduction heterogeneity. Conditioned medium (Cme) of (co)cultures was used to assess paracrine mechanisms.ResultsMicrospheres did not affect CV in control (NRVM) monolayers. In co-cultures of NRVM and rASC, hASC or pASC, CV was lower than in controls (14.4±1.0, 13.0±0.6 and 9.0± 1.0 vs. 19.5±0.5 cm/s respectively, p<0.001). Microspheres loaded with either rASC or hASC still induced conduction slowing compared to controls (13.5±0.4 and 12.6±0.5 cm/s respectively, p<0.001). However, pASC loaded microspheres increased CV of NRVM compared to pASC and NRMV co-cultures (16.3±1.3 cm/s, p< 0.001) and did not differ from controls (p = NS). Cme of pASC reduced CV in control monolayers of NRVM (10.3±1.1 cm/s, p<0.001), similar to Cme derived from pASC-loaded microspheres (11.1±1.7 cm/s, p = 1.0). The presence of microspheres in monolayers of NRVM abolished the CV slowing influence of Cme pASC (15.9±1.0 cm/s, p = NS vs. control).ConclusionThe application of recombinant human collagen-based microspheres mitigates indirect paracrine conduction slowing through interference with a secondary autocrine myocardial factor.