Structural Characteristics of Small Intestinal Submucosa Constructs Dictate In Vivo Incorporation and Angiogenic Response

Abstract

The rate of angiogenesis and cellular infiltration into degradable biomaterials determines scaffold persistence in vivo. The ability to tune the degradation properties of naturally derived biomaterials has been a popular goal in tissue engineering, yet has often depended on chemical crosslinking. Small intestinal submucosa (SIS) is a naturally derived, collagen-based, bioactive scaffold that has broad clinical success in many therapeutic applications. Two methods for producing multilayer, non-crosslinked SIS constructs were compared in vitro and in vivo. Traditional and cryo SEM, mercury intrusion porosimetry, and a novel enzymatic degradation assay determined that lyophilization produced an open, porous scaffold, in contrast to the collapsed, denser structure of SIS constructs produced using a vacuum press process. The angiogenic responses to lyophilized and vacuum-pressed SIS constructs were evaluated in vivo using a subcutaneous implant assay in mice. Explanted samples were compared after 7 and 21 days using fluorescence microangiography and light microscopy. Capacity of the implant neovasculature was also determined. These experiments revealed that the lyophilized SIS was infiltrated and vascularized more rapidly than the vacuum pressed. These data demonstrate the tunable incorporation of a non-crosslinked ECM-based biomaterial, which may have implications for the persistence of this degradable scaffold in tissue engineering.

Implantation of VEGF‐functionalized cell‐free vascular grafts: regenerative and immunological response

“…In this study, we utilized the clinical grade biomaterial known as decellularized porcine SIS, which has been used extensively in the past (24,(37)(38)(39)(40)(41)(42). Using SIS with immobilized heparin and VEGF, we developed cell-free off-theshelf vascular grafts with submillimeter inner diameters (850-900 mm) that were implanted into the arterial system of a mouse.…”

A Gingiva-Derived Mesenchymal Stem Cell-Laden Porcine Small Intestinal Submucosa Extracellular Matrix Construct Promotes Myomucosal Regeneration of the Tongue

“…52,54 The decellularized gastrointestinal small intestine submucosa (SIS) is among the most commonly used acellular scaffolds that display a comparable level of skeletal muscle regenerative capacity to a skeletal muscle-derived decellularized ECM. 28,[53][54][55] The pre-and clinical successful use of SIS-ECM in tissue reconstruction might be due to its special three-dimensional ECM structure, 56 components of inherent bioactive molecules, 57 and the biodegradability that can foster its integration with host tissues. 58 In addition, matrix-derived cell signaling molecules, including certain cytokines and growth factors, may play an important role in modulating fibrosis, 20 inflammation, 59,60 angiogenesis, 13,56,61,62 and other pathophysiological processes that are critical for tissues to initiate an optimal regenerative response.…”

Mesenchymal Stem Cell Seeding of Porcine Small Intestinal Submucosal Extracellular Matrix for Cardiovascular Applications

“…Previous efforts using cell therapy have met with limited clinical success due to poor cell retention rate post-implantation or injection [ 43 , 44 ]. A porous biomaterial [ 19 ], such as SIS-ECM, capable of supporting cell repopulation and growth has the potential to act as a delivery vehicle, improving cell retention rate in vivo while still allowing the repopulated cells to migrate within the local injury site. The maximum loading density of hMSCs on the FDA-approved porcine SIS-ECM material was found to be 350,000 cells per cm 2 without affecting cell viability ( Fig 1A ).…”

“…Several animal and clinical studies have demonstrated the ability of decellularized porcine SIS-ECM to mediate tissue repair in a range of regenerative applications, including wound healing [ 1 – 4 ], bladder regeneration [ 5 – 7 ], tendon graft [ 8 ] gastrointestinal grafts [ 9 – 11 ] and cardiovascular repairs [ 12 – 18 ]. The clinical success of this collagen-rich biomaterial has been suggested to correlate with its micro three-dimensional ECM structural environment [ 19 ], bioactive molecules within the material [ 20 ] and its biodegradability which fosters integration with host tissue [ 14 ]. Additionally, matrix-derived cell signaling molecules (cytokines and growth factors) have been demonstrated to play an important role in modulating fibrosis [ 2 ], inflammation [ 21 , 22 ] and promoting angiogenesis [ 19 , 23 – 25 ] which can be critical to mediate tissue regenerative responses.…”

“…The clinical success of this collagen-rich biomaterial has been suggested to correlate with its micro three-dimensional ECM structural environment [ 19 ], bioactive molecules within the material [ 20 ] and its biodegradability which fosters integration with host tissue [ 14 ]. Additionally, matrix-derived cell signaling molecules (cytokines and growth factors) have been demonstrated to play an important role in modulating fibrosis [ 2 ], inflammation [ 21 , 22 ] and promoting angiogenesis [ 19 , 23 – 25 ] which can be critical to mediate tissue regenerative responses.…”