Small Intestinal Submucosa Extracellular Matrix Research Articles

Mechanical and Geometric Characterization of a Novel 2-Ply Vacuum-Pressed Biological Scaffold Patch Design for Posterior Mitral Valve Reconstruction.

To assess the mechanical properties of small intestinal submucosal extracellular matrix (SIS-ECM) iterations and choose the optimal version for evaluating functional geometrics after posterior mitral valve reconstruction. Four SIS-ECM versions (2- and 4-ply vacuum-pressed and lyophilized) underwent uniaxial tensile testing. A posterior mitral valve reconstruction patch was developed based on MRI scans (n = 5). Posterior mitral valve reconstruction using 2-ply vacuum-pressed SIS-ECM was performed (n = 7), and geometrics were evaluated using a modified left heart simulator. The vacuum-pressed iterations displayed superior maximum stress values compared to lyophilized (2-ply: median [IQR], 15.8 [15.2-19.0] vs 7.9 [7.3-8.3] MPa, p < 0.001; 4-ply: median (IQR), 15.8 -[14.6-22.0] vs 7.9 [7.6-8.4] MPa). All reconstructed valves were competent with preserved total leaflet area, but individual leaflet segment areas were redistributed. Posterior mitral valve reconstruction with our 2-ply vacuum-pressed SIS-ECM patch design was feasible in vitro. Further in vivo evaluation is warranted.

One-Year Outcome of an Ongoing Pre-Clinical Growing Animal Model for a Tissue-Engineered Valved Pulmonary Conduit.

Objectives: A self-constructed valved pulmonary conduit made out of a de-cellularized porcine small intestinal submucosal extracellular matrix biological scaffold was tested in a chronic growing lamb model. Methods: The conduit was implanted in pulmonary valve position in 19 lambs. We monitored clinical, laboratory, and echocardiographic findings until 12 months after surgery. In two animals, euthanasia was planned at nine and twelve months. Pre-mortem chest computed tomography and post-mortem pathologic work up were performed. Data are presented as frequency and percentage, median and range, or mean and standard deviation. Results: Twelve (63.2%) animals survived the perioperative period. Three unexpected deaths occurred during the follow-up period: one due to aspiration pneumonia at 23 days after surgery, and two due to early and late infective endocarditis of the conduit at 18 and 256 days. In the two animals with planned scarification, the pre-mortem CT scan revealed mild or no calcification within the conduit or valve leaflets. In the echocardiographic examination at 12 months, peak and mean systolic pressure gradients across the conduit valve were 6.5 (3-21) mmHg and 3 (2-12) mmHg, while valve regurgitation was none (n = 2), trivial (n = 5), moderate (n = 1), or severe (n = 1). No clinical or laboratory signs of hemolysis were seen. After 12 months of follow-up, the animals' body weights had increased from 33 (27-38) kg to 53 (38-66) kg (p = 0.010). Conclusions: Implantation of a valved pulmonary conduit in our growing lamb model was feasible. Infective endocarditis of the implanted valved conduit remained a significant complication.

Engineering Tumor Stroma Morphogenesis Using Dynamic Cell-Matrix Spheroid Assembly.

The tumor microenvironment consists of resident tumor cells organized within a compositionally diverse, three-dimensional (3D) extracellular matrix (ECM) network that cannot be replicated in vitro using bottom-up synthesis. We report a new self-assembly system to engineer ECM-rich 3D MatriSpheres wherein tumor cells actively organize and concentrate microgram quantities of decellularized ECM dispersions which modulate cell phenotype. 3D colorectal cancer (CRC) MatriSpheres were created using decellularized small intestine submucosa (SIS) as an orthotopic ECM source that had greater proteomic homology to CRC tumor ECM than traditional ECM formulations such as Matrigel. SIS ECM was rapidly concentrated from its environment and assembled into ECM-rich 3D stroma-like regions by mouse and human CRC cell lines within 4-5 days via a mechanism that was rheologically distinct from bulk hydrogel formation. Both ECM organization and transcriptional regulation by 3D ECM cues affected programs of malignancy, lipid metabolism, and immunoregulation that corresponded with an in vivo MC38 tumor cell subpopulation identified via single cell RNA sequencing. This 3D modeling approach stimulates tumor specific tissue morphogenesis that incorporates the complexities of both cancer cell and ECM compartments in a scalable, spontaneous assembly process that may further facilitate precision medicine.

Entire Mitral Valve Reconstruction Using Porcine Extracellular Matrix: Adding a Ring Annuloplasty

PurposeThis study investigated the implications of inserting a flexible annuloplasty ring after reconstructing the entire mitral valve in a porcine model using a previously investigated tube graft design made of 2-ply small intestinal submucosa extracellular matrix (CorMatrix®).MethodsAn acute model with eight 80-kg pigs, each acting as its own control, was used. The entire mitral valve was reconstructed with a 2-ply small intestinal submucosa extracellular matrix tube graft (CorMatrix®). Subsequently, a Simulus® flexible ring was inserted. The characterization was based on mitral annular geometry and valvular dynamics with sonomicrometry and echocardiography.ResultsAfter adding the ring annuloplasty, the in-plane annular dynamics were more constant throughout the cardiac cycle compared to the reconstruction alone. However, the commissure–commissure distance was statistically significantly decreased [35.0 ± 3.4 mm vs. 27.4 ± 1.9 mm, P < 0.001, diff = − 7.6 mm, 95% CI, − 9.8 to (−5.4) mm] after ring insertion, changing the physiological annular D-shape into a circular shape which created folds at the coaptation zone resulting in a central regurgitant jet on color Doppler.ConclusionWe successfully reconstructed the entire mitral valve using 2-ply small intestinal submucosal extracellular matrix (CorMatrix®) combined with a flexible annuloplasty. The annuloplasty reduced the unphysiological systolic widening previously found with this reconstructive technique. However, the Simulus flex ring changed the physiological annular D-shape into a circular shape and hindered a correct unfolding of the leaflets. Thus, we do not recommend a flexible ring in conjunction with this reconstructive technique; further investigations are needed to discover a more suitable remodelling annuloplasty.

Composite Biosynthetic Graft for Repair of Long-Segment Tracheal Stenosis: A Pilot In Vivo and In Vitro Feasibility Study.

Pediatric patients who undergo surgery for long-segment congenital tracheal stenosis (LSCTS) have suboptimal outcomes and postsurgical complications. To address this, we propose a biosynthetic graft comprising (1) a porcine small intestinal submucosa extracellular matrix (SIS-ECM) patch for tracheal repair, and (2) a resorbable polymeric exostent for biomechanical support. The SIS-ECM patch was evaluated in vivo in an ovine trachea model over an 8 month period. Concurrently, the biosynthetic graft was evaluated in a benchtop lamb trachea model for biomechanical stability. In vivo results show that SIS-ECM performs better than bovine pericardium (control) by preventing granulation tissue/restenosis, restoring tracheal architecture, blood vessels, matrix components, pseudostratified columnar and stratified epithelium, ciliary structures, mucin production, and goblet cells. In vitro tests show that the biosynthetic graft can provide the desired axial and flexural stability, and biomechanical function approaching that of native trachea. These results encourage future studies to evaluate safety and efficacy, including biomechanics and collapse risk, biodegradation, and in vivo response enabling a stable long-term tracheal repair option for pediatric patients with LSCTS and other tracheal defects.

Small intestinal submucosa extracellular matrix: advantages, evidence and application.

Small intestinal submucosa extracellular matrix: advantages, evidence and application.

Preparation and characterization of a novel composite acellular matrix/hyaluronic acid thermosensitive hydrogel for interstitial cystitis/bladder pain syndrome.

Bladder mucosa damage that causes harm to the interstitium is a recognized pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). The intravesical instillation of drugs is an important second-line therapy, but it is often necessary to use drugs repeatedly in the clinic because of their short residence time in the bladder cavity, which alters the therapeutic effect. To overcome this drawback, this study developed a novel composite acellular matrix/hyaluronic acid (HA) thermosensitive hydrogel (HA-Gel) using rabbit small intestinal submucosa extracellular matrix (ECM) as the thermosensitive material and HA as the drug component and examined its composition, microstructure, thermodynamic properties, temperature sensitivity, rheological properties, biocompatibility, drug release, hydrogel residue, and bacteriostatic properties. The study showed HA-Gel was liquid at temperatures of 15-37.5°C and solid at 37.5-50°C, its swelling rate decreased with increasing temperature, and its lower critical solution temperature occurred at approximately 37.5°C. This property made the hydrogel liquid at room temperature convenient for intravesical perfusion and turned into a solid about 1 min after entering the body and rising to body temperature to increase its residence time. Subsequent experiments also proved that the gel residue time of HA-Gel in vivo and the drug release time of HA in vivo could reach more than 5 days, which was significantly higher than that of HA alone, and it had good biocompatibility and antibacterial properties. Therefore, this hydrogel possesses the proper characteristics to possibly make it an ideal dosage form for IC/BPS intravesical instillation therapy.

Hand-Constructed CorMatrix Tubular Valve Used for Tricuspid Valve Replacement in Neonate With Congenital Tricuspid Dysplasia: Five-Year Follow-Up.

Tricuspid valve (TV) dysplasia is a rare congenital defect that, in severe cases, can cause heart failure necessitating surgical correction. TV replacement options are limited in neonates since few commercial valves are available and the rates of failure and postoperative mortality are high. The authors report a neonate with TV dysplasia who underwent replacement with a hand-constructed tube valve using small intestinal submucosal extracellular matrix, which functioned well for >5 years.

Successful Use of Acellular Small Intestinal Submucosa Graft in Vaginal Reconstruction

PurposeVarious techniques for neovaginal construction have been employed in the pediatric and adult populations, including the use of intestinal segments, buccal mucosal grafts, and skin grafts. Small intestinal submucosa (SIS) extracellular matrix grafts have been described as a viable alternative, though prior experience is limited. Our purpose was to assess operative characteristics and patient outcomes with neovaginal construction using SIS grafts. MethodsThirteen patients underwent vaginoplasty with acellular porcine SIS grafts at our institution between 2018 and 2022. Operative and clinical data, postoperative mold management, vaginal dilating length, and complications were reviewed. ResultsAge at time of repair ranged from 13 to 30 years (median 19 years). Patient diagnosis included cloacal anomalies (n = 4), Mayer-Rokitansky-Küster-Hauser syndrome (n = 4), isolated vaginal atresia with or without a transverse vaginal septum (n = 4), and vaginal rhabdomyosarcoma requiring partial vaginectomy (n = 1). Following dissection of the neovaginal space, a silicon mold wrapped with SIS graft was placed with retention sutures and removed on postoperative day 7. Median (IQR) operative time was 171 (118–192) minutes, estimated blood loss was 10 (5–20) mL, and length of stay was 2 (1–3) days. The follow-up period ranged from 3 to 47 months (median 9 months). Two patients developed postoperative vaginal stenosis that resolved with dilation under anesthesia. Mean vaginal length on latest follow-up was 8.97 cm. All thirteen patients had successful engraftment and progressed to performing self-dilations or initiating intercourse to maintain patency. There were no cases of graft reaction or graft extrusion. ConclusionsWe conclude that acellular small intestinal submucosa grafts are effective and safe alternatives for mold coverage in neovaginal construction. Our experience demonstrates minimal perioperative morbidity, early mold removal, and progression to successful dilation with maintenance of a functional vaginal length. Future study on sexual outcomes, patient satisfaction, and comparison against alternative techniques has been initiated. Level of EvidenceIV. Type of StudyRetrospective Study.

Practical applications of small intestine submucosa extracellular matrix (SIS-ECM) an expert panel consensus.

Practical applications of small intestine submucosa extracellular matrix (SIS-ECM) an expert panel consensus.

Biomechanical comparison of porcine mitral leaflets with porcine small intestinal submucosa extracellular matrix.

Porcine small intestinal submucosa extracellular matrix (SIS-ECM) used for cardiac valve repair has shown conflicting clinical outcomes with respect to calcification and failure. This may be related to differences in biomechanical properties of the material compared with the host site. The aim of this study was to compare the biomechanical properties of porcine mitral valve leaflets with SIS-ECM. Fresh porcine anterior and posterior mitral leaflet samples were cut radially and circumferentially. Similarly, 2- and 4-layered SIS-ECM were cut in orthogonal directions: length and width. Samples were subjected to a uniaxial tensile test or a dynamic mechanical analysis. Results show that the load of the porcine anterior circumferential leaflet was 39.5 N (2.4-48.5 N), which was significantly higher compared with the 2-layered length SIS-ECM which was 7.5 N (7-7.9 N), and the 4- layered length SIS-ECM which was 7.5 N (7.1-8.1 N) (p < 0.001). The load of the posterior circumferential leaflet was 9.7 N (8.3-10.7 N), which is still significantly higher when compared with the two versions of SIS-ECM. The degree of anisotropy (i.e. the ratio between circumferential-radial and width-length properties) was higher for the anterior- (ratio: 19) and posterior leaflet (ratio: 6) than the 2-layered (ratio: 5.1) and 4-layered SIS-ECM (ratio: 1.9). Especially 2-layered SIS-ECM more closely resembles the posterior mitral leaflet than the anterior mitral leaflet tissue and would be more suitable as a repair material in this position. Additionally, the anisotropic properties of mitral leaflets and SIS-ECM underscore the importance of correct orientation of the implant to ensure optimal reconstruction.

Acellular biomaterial modulates myocardial inflammation and promotes endogenous mechanisms of postinfarct cardiac repair.

After myocardial infarction, we previously showed that epicardial implantation of porcine small intestinal submucosal extracellular matrix (SIS-ECM) improves postinfarct cardiac function through fibroblast-mediated angiogenic and antifibrotic pathways. Herein, we characterize how SIS-ECM also coordinates a reparative cardiac inflammatory response. RNA sequencing and multiplex characterized modulation of fibroblast transcriptional and paracrine activity by SIS-ECM. Inhibitors of fibroblast growth factor 2 and toll-like receptor 9 elucidated mechanism. Mice received coronary ligation (infarction) and either SIS-ECM implantation (treatment) or sham surgery (control). Flow cytometry of SIS-ECM and the murine myocardium quantified monocytes, neutrophils, and proangiogenic subtypes. Microscopy tracked fibroblasts and immune cells, and characterized myocardial angiogenesis. SIS-ECM increased fibroblast transcription of inflammatory pathways and production of angiogenic vascular endothelial growth factor and inflammatory cytokines via fibroblast growth factor 2 and toll-like receptor 9-dependent pathways. Two-photon microscopy showed that SIS-ECM became engrafted by native fibroblasts and leukocytes, subsequently increasing release of inflammatory cytokines and angiogenic vascular endothelial growth factor. On flow cytometry, SIS-ECM implantation increased day-7 myocardial counts of neutrophils, inflammatory monocytes, and proangiogenic vascular endothelial growth factor recptor 1 subtypes. SIS-ECM has a higher proportion of proangiogenic leukocytes compared with the myocardium. Resonant confocal microscopy showed neovascularization near SIS-ECM. SIS-ECM promotes engraftment by native fibroblasts and leukocytes, and modulates fibroblast activity via fibroblast growth factor 2 and toll-like receptor 9 to potentiate a proangiogenic inflammatory response. Subsequently, the material increases myocardial counts of reparative proangiogenic leukocytes that can induce neovascularization. This reparative inflammatory response may explain previously reported functional improvements. Fibroblast growth factor 2 and toll-like receptor 9 mechanisms can be leveraged to design next-generation materials for postinfarct cardiac repair.

Role of small intestinal submucosa extracellular matrix in advanced regenerative wound therapy.

Advanced regenerative therapies using cellular and tissue-based products (CTPs) can play an important role in effective management of hard-to-heal wounds. CTPs derived from allogenic or xenogenic tissues use an extracellular matrix (ECM) to provide a therapeutic ECM scaffold in the wound bed to facilitate tissue regeneration. One such example is OASIS Extracellular Matrix (Cook Biotech Incorporated), a porcine small intestinal submucosa extracellular matrix (SIS-ECM) that preclinical and clinical data have shown to be tolerable and effective in promoting tissue regeneration in hard-to-heal wounds.

Role of small intestinal submucosa extracellular matrix in advanced regenerative wound therapy.

Advanced regenerative therapies using cellular and tissue-based products (CTPs) can play an important role in effective management of hard-to-heal wounds. CTPs derived from allogenic or xenogenic tissues use an extracellular matrix (ECM) to provide a therapeutic ECM scaffold in the wound bed to facilitate tissue regeneration. One such example is OASIS Extracellular Matrix (Cook Biotech Incorporated), a porcine small intestinal submucosa extracellular matrix (SIS-ECM) that preclinical and clinical data have shown to be tolerable and effective in promoting tissue regeneration in hard-to-heal wounds.

Clinical benefits of small intestinal submucosa extracellular matrix and review of the evidence.

There is a clear scientific rationale for using cellular, acellular and matrix-like products (CAMPs), such as small intestinal submucosa extracellular matrix (SIS-ECM), in hard-to-heal wounds, such as diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), pressure ulcers and arterial leg ulcers. The clinical evidence supporting the use of SIS-ECM has grown over the past several decades. This evidence base now encompasses a wide range of hard-to-heal wound indications, including DFUs and VLUs, as well as increasingly complex acute wound indications, such as delayed postoperative wounds, traumatic wounds and burns. The aim of this article is to review the steadily amassed body of evidence that describes the clinical outcomes associated with treatment with SIS-ECM and its potential implications for the overall costs of treatment.

Clinical benefits of small intestinal submucosa extracellular matrix and review of the evidence.

There is a clear scientific rationale for using cellular, acellular and matrix-like products (CAMPs), such as small intestinal submucosa extracellular matrix (SIS-ECM), in hard-to-heal wounds, such as diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), pressure ulcers and arterial leg ulcers. The clinical evidence supporting the use of SIS-ECM has grown over the past several decades. This evidence base now encompasses a wide range of hard-to-heal wound indications, including DFUs and VLUs, as well as increasingly complex acute wound indications, such as delayed postoperative wounds, traumatic wounds and burns. The aim of this article is to review the steadily amassed body of evidence that describes the clinical outcomes associated with treatment with SIS-ECM and its potential implications for the overall costs of treatment.

Application expansion of small intestinal submucosa extracellular matrix in complex and surgical wounds.

A wound is hard-to-heal or complex when the defect fails to progress through the normal stages of wound healing in a timely fashion. Hard-to-heal wounds such as diabetic foot or venous leg ulcers can be long-lasting conditions. Alternatively, complex acute wounds that occur from trauma, burns, postoperative, necrosis and some dermatological diseases can also result in hard-to-heal wounds. This article reviews important considerations in the management of complex acute wounds, such as time to wound closure, pain, scarring, patient satisfaction and identification of options that can promote healing of grafts and flaps, while reducing donor-site morbidity. Primary research has demonstrated the inherent benefits of small intestinal submucosa extracellular matrix (SIS-ECM), a naturally occurring porcine matrix that promotes development of dermis-like tissue in both complex acute and hard-to-heal wounds. Presently, the literature provides mostly case studies demonstrating the benefits of SIS-ECM in the management of complex acute wounds. The available case series suggest emerging clinical benefits including rapid time to coverage, avoidance of donor-site complications and development of granulation tissue in locations of low circulation, which improves poor graft sites, potentially reducing dehiscence and providing support for reconstruction flaps and grafts.

PERICARDIAL DELIVERY OF MICRONIZED MATRIX BIOMATERIAL LEVERAGES AN EOSINOPHIL IMMUNE RESPONSE FOR POST-INFARCT CARDIAC REPAIR

Ischemic heart disease (IHD) remains a leading cause of mortality. After myocardial infarction (MI), immune cell functions and phenotypes mediate maladaptive tissue remodeling with progression to heart failure. Extracellular matrix (ECM) biomaterials can modulate immune cell phenotypes and may optimize repair. Pericardial fluid contains pro-reparative immune cells that ECM biomaterials may stimulate to promote adaptive remodeling and preserve post-infarct cardiac function. Herein, we explore the impact of pericardial delivery of a micronized ECM biomaterial (porcine small intestinal submucosal extracellular matrix; mSIS-ECM) on post-infarct cardiac inflammation and tissue healing.

Inductive Remodeling of Extracellular Matrix Scaffolds in the Temporomandibular Joint of Pigs.

The temporomandibular joint (TMJ) disc is a fibrocartilaginous tissue located between the condyle of the mandible and glenoid fossa and articular eminence of the temporal bone. Damage or derangement of the TMJ disc can require surgical removal (discectomy) to restore function. Removal of the TMJ disc, however, leaves the joint space vulnerable to condylar remodeling and degradation, potentially leading to long-term complications. No consistently effective clinical option exists for repair or replacement of the disc following discectomy. This study investigates the use of an acellular scaffold composed of extracellular matrix (ECM) derived from small intestinal submucosa (SIS) as a regenerative template for the TMJ disc in a porcine model. Acellular SIS ECM scaffolds were implanted following discectomy and allowed to remodel for 2, 4, 12, and 24 weeks postimplantation. Remodeling of the implanted device was assessed by longitudinal magnetic resonance imaging (MRI) over the course of 6 months, as well as gross morphologic, histologic, biochemical, and biomechanical analysis (tension and compression) of explanted tissues (disc and condyle) at the time of sacrifice. When the scaffold remained in the joint space, longitudinal MRI demonstrated that the scaffolds promoted new tissue formation within the joint space throughout the study period. The scaffolds were rapidly populated with host-derived cells and remodeled with formation of new, dense, aligned fibrocartilage resembling native tissue as early as 1 month postimplantation. De-novo formation of peripheral muscular and tendinous attachments resembling those in native tissue was also observed. The remodeled scaffolds approached native disc biochemical composition and compressive modulus, and possessed 50% of the tensile modulus within 3 months postimplantation. No degradation of the condylar surface was observed. These results suggest that this acellular bioscaffold fills a medical need for which there is currently no effective treatment and may represent a clinically relevant "off-the-shelf" implant for reconstruction of the TMJ disc.

Abstract 10751: Pericardial Injection of Micronized Matrix Biomaterial Improves Post-Infarct Cardiac Function and Modulates Fibroblast Activity to Enhance Repair

Introduction: Injection of micronized biomaterials into the pericardial space leverages bioinductive properties to enhance post-infarct cardiac repair. This less invasive, potentially bedside, approach enables early intervention. Micronized porcine small intestinal submucosal extracellular matrix (SIS-ECM) contains fibroblast growth factor 2 (FGF2) which reduce fibrosis and increase vasculogenesis. Hypothesis: Pericardial delivery of micronized SIS-ECM improves post-infarct cardiac function. It promotes a proangiogenic and antifibrotic fibroblast phenotype. Methods: Mice received coronary ligation (infarct) through an undisrupted pericardium followed by pericardial delivery of micronized SIS-ECM or saline control. Pressure-volume loops were at 28 days. Myocardial isolectin stain assessed small vessel density on confocal microscopy. Mouse 3T3 cell line fibroblasts in 3D collagen matrices were exposed to biomaterial-conditioned media or media control. Multiplex analyzed paracrine activity. Collagen gel contraction and MMP2 production assessed profibrotic phenotype. FGF2 inhibitor elucidated mechanism. Results: Mice receiving micronized SIS-ECM had lower ventricular stiffness (0.23±0.03 vs 0.39±0.05 mmHg/uL; p=0.01), higher ejection fraction (34.7±2.5 vs 26.9±2.8%; p&lt;0.05) and higher stroke work (1510±138 vs 1066±152 μL/mmHg; p=0.04). The SIS-ECM group had higher normalized border zone isolectin mean fluorescence (0.82±0.04 vs 0.58±0.06; p=0.01). Micronized SIS-ECM attenuated collagen gel contraction (26±6 vs 56±5%; p=0.01) and MMP2 release (66±2 vs 83±3 ng/mL; p&lt;0.01). Micronized SIS-ECM increased fibroblast VEGF production (904±79 vs 628±25; pg/mL). FGF2 inhibitor negated biomaterial effects, increasing gel contraction (27.3±5.3 vs 11.0±0.5%; p=0.04; inhibitor vs no inhibitor) and MMP-2 release (141±8 vs 100±6 ng/mL; p=0.02). Conclusions: Pericardial injection of micronized SIS-ECM attenuates profibrotic fibroblast activity, increases release of angiogenic VEGF protein, increases vasculogenesis on isolectin staining, and preserves post-infarct cardiac function. This less invasive strategy facilitates early intervention to attenuate maladaptive post-infarct structural remodeling.