Small Intestinal Submucosa Research Articles

Degassing a Decellularized Scaffold Enhances Wound Healing and Reduces Fibrosis during Tracheal Defect Reconstruction: A Preliminary Animal Study

Few efforts have been made regarding the optimization of porcine small intestinal submucosa (SIS) to improve its biocompatibility. This study aims to evaluate the effect of SIS degassing on the promotion of cell attachment and wound healing. The degassed SIS was evaluated in vitro and in vivo, compared with the nondegassed SIS control. In the cell sheet reattachment model, the reattached cell sheet coverage was significantly higher in the degassed SIS group than in the nondegassed group. Cell sheet viability was also significantly higher in the SIS group than in the control group. In vivo studies showed that the tracheal defect repaired by the degassed SIS patch showed enhanced healing and reductions in fibrosis and luminal stenosis compared to the nondegassed SIS control group, with the thickness of the transplanted grafts in the degassed SIS group significantly lower than those in the control group (346.82 ± 28.02 µm vs. 771.29 ± 20.41 µm, p < 0.05). Degassing the SIS mesh significantly promoted cell sheet attachment and wound healing by reducing luminal fibrosis and stenosis compared to the nondegassed control SIS. The results suggest that the degassing processing might be a simple and effective way to improve the biocompatibility of SIS.

Three dimensional printed wound dressings: recent progresses.

Three dimensional printed wound dressings: recent progresses.

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.

Bioactive ECM-Loaded SIS Generated by the Optimized Decellularization Process Exhibits Skin Wound Healing Ability in Type I Diabetic Rats.

Patients with diabetes have 15-25% chance for developing diabetic ulcers as a severe complication and formidable challenge for clinicians. Conventional treatment for diabetic ulcers is to surgically remove the necrotic skin, clean the wound, and cover it with skin flaps. However, skin flap often has a limited efficacy, and its acquisition requires a second surgery, which may bring additional risk for the patient. Skin tissue engineering has brought a new solution for diabetic ulcers. Herein, we have developed a bioactive patch through a compound culture and the optimized decellularization strategy. The patch was prepared from porcine small intestinal submucosa (SIS) and modified by an extracellular matrix (ECM) derived from urine-derived stem cells (USCs), which have low immunogenicity while retaining cytokines for angiogenesis and tissue regeneration. The protocol included the optimization of the decellularization time and the establishment of the methods. Furthermore, the in vitro mechanism of wound healing ability of the patch was investigated, and its feasibility for skin wound healing was assessed through an antishrinkage full-thickness skin defect model in type I diabetic rats. As shown, the patch displayed comparable effectiveness to the USCs-loaded SIS. Our findings suggested that this optimized decellularization protocol may provide a strategy for cell-loaded scaffolds that require the removal of cellular material while retaining sufficient bioactive components in the ECM for further applications.

Uniformly doped bioactive strontium ions chelate extracellular matrix scaffolds for bone repair

This paper describes a novel natural extracellular matrix-derived scaffold composite prepared through a coordination reaction between small intestinal submucosa (SIS) and strontium (Sr) ions. The physicochemical and biological properties of the Sr/SIS composite scaffold were investigated. The Sr/SIS complex had a porous structure and a uniform distribution of Sr2+. The coordination bond of Sr-SIS provides the Sr/SIS scaffolds with improved mechanical properties and sustained Sr2+ release.Controlled release of Sr2+ enhanced cell proliferation and osteogenic differentiation. The 1.5 wt% Sr/SIS scaffold had the best osteogenesis effect among the experimental groups, indicating its potential as a biomaterial for bone tissue engineering.

The long-term outcomes of vaginoplasty using acellular porcine small intestinal submucosa grafts in patients with Mayer-Rokitansky-Küster-Hauser syndrome: A case series.

To investigate the long-term outcomes for Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) patients undergoing vaginoplasty using acellular porcine small intestinal submucosa grafts (SIS). A case series. Seventy-eight MRKH syndrome patients and a post-SIS patient who delivered a baby following the world's first robot-assisted uterus transplantation. Mayer-Rokitansky-Küster-Hauser syndrome patients were grouped based on the postoperative time and the diagnosis-surgery interval. Outcomes of sexual function and psychological status were assessed using the female sexual function index (FSFI), self-rating scale of body image (SSBI) and self-acceptance questionnaire (SAQ). Anatomical outcomes were measured by clinicians. The primary outcome was restoration of sexual function, defined by an FSFI score in the 'good' range. Anatomical and psychological outcomes were also analysed. Sexual function was restored in 42.3% (33/78) of patients and the total FSFI score was 23.44 ± 4.43. Three factors (body defect, recognition of physical appearance and willingness to change physical appearance scores) in the SSBI and two in the SAQ decreased as the postoperative time increased. Based on the interval between diagnosis and surgery, the total SSBI score was lower in the short-interval group than in the long-interval group (7.25 ± 5.55 versus 12.04 ± 10.21, p=0.038). Nearly half of MRKH patients in our study had good long-term sexual function after SIS vaginoplasty. Sexual function and psychological status improved as postoperative time increased. In addition, reducing the diagnosis to surgery interval was associated with improved psychological function.

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.

Bioactive photocrosslinkable resin solely based on refined decellularized small intestine submucosa for vat photopolymerization of in vitro tissue mimics

Three-dimensionally (3D) printed tissue mimics are unique in vitro platforms for studying human pathophysiology in a more physiologically relevant manner compared to oversimplified 2D cell cultures and complex animal models. However, their 3D printing requires an availability of materials that at the same time show a high level of biomimicry and also have a suitable viscosity profile and crosslinking kinetics for the desired printing technique. We developed a new biomimetic material for vat photopolymerization by solubilizing and functionalizing porcine small intestine submucosa (dSIS) into photocrosslinkable dSIS methacryloyl (dSIS-MA) and by subsequently formulating it into a bioactive 3D printing resin. The concentration of 1.5 wt% of dSIS-MA yielded desired viscosity and photocrosslinking kinetics, and the 3D printing of the resin resulted in fully transparent and highly swelling dSIS-MA hydrogels with a stiffness resembling native intestinal tissue. The new dSIS-MA resin was successfully 3D printed into acellular intestine-mimicking scaffolds that desirably guided the seeded human intestinal cells to grow along the 3D villi mimics. Human small intestinal organoid-derived undifferentiated primary cells grew to confluency on the dSIS-MA hydrogels and formed continuous tight junctions, thereby demonstrating the suitability of the 3D printing material for growing intestinal epithelium mimics. Furthermore, a small fraction of the human primary intestinal cells produced mucin 5AC, demonstrating early differentiation of these cells on the dSIS-MA hydrogels. The excellent cell compatibility of the dSIS-MA material combined with its high printability and biomimicry indicated that this new resin can be a great help in modelling and reproducing native tissue architectures where enhanced physiological relevancy is desired.

Obscure Gastrointestinal Bleeding Caused by a Small Intestinal Lymphatic-venous Malformation: A Case Report with a Literature Review

A 44-year-old woman presented with severe anemia. We strongly suspected gastrointestinal bleeding; however, esophagogastroduodenoscopy, colonoscopy, and computed tomography showed no bleeding sources. Video capsule endoscopy revealed an actively bleeding submucosal lesion within the jejunum. Double-balloon enteroscopy revealed a 20-mm continuously bleeding submucosal lesion in the distal jejunum. We suspected small intestinal vascular malformation and performed surgical resection. The resected specimen pathologically comprised dilated, thin-walled lymphatic channels and blood vessels involving the small intestinal submucosa. Therefore, the patient was diagnosed with small intestinal lymphatic-venous malformation. Postoperatively, the patient recovered well, and recurrence was not observed.

Unraveling the Relevance of Tissue-Specific Decellularized Extracellular Matrix Hydrogels for Vocal Fold Regenerative Biomaterials: A Comprehensive Proteomic and In Vitro Study.

Decellularized extracellular matrix (dECM) is a promising material for tissue engineering applications. Tissue-specific dECM is often seen as a favorable material that recapitulates a native-like microenvironment for cellular remodeling. However, the minute quantity of dECM derivable from small organs like the vocal fold (VF) hampers manufacturing scalability. Small intestinal submucosa (SIS), a commercial product with proven regenerative capacity, may be a viable option for VF applications. This study aims to compare dECM hydrogels derived from SIS or VF tissue with respect to protein content and functionality using mass spectrometry-based proteomics and in vitro studies. Proteomic analysis reveals that VF and SIS dECM share 75% of core matrisome proteins. Although VF dECM proteins have greater overlap with native VF, SIS dECM shows less cross-sample variability. Following decellularization, significant reductions of soluble collagen (61%), elastin (81%), and hyaluronan (44%) are noted in VF dECM. SIS dECM contains comparable elastin and hyaluronan but 67% greater soluble collagen than VF dECM. Cells deposit more neo-collagen on SIS than VF-dECM hydrogels, whereas neo-elastin (~50 μg/scaffold) and neo-hyaluronan (~ 6 μg/scaffold) are comparable between the two hydrogels. Overall, SIS dECM possesses reasonably similar proteomic profile and regenerative capacity to VF dECM. SIS dECM is considered a promising alternative for dECM-derived biomaterials for VF regeneration.

Acceleration of wound healing by composite small intestinal submucosa hydrogels through immunomodulation

Small intestinal submucosa (SIS) hydrogel is a potential candidate for wound dressing since its excellent biocompatibility and bioactivities. However, the intrinsic lack of sufficient immunomodulatory activities has limited its application. Herein, tannic acid (TA) and interleukin-10 (IL-10) were supplemented to the SIS hydrogel to fabricate a novel composite hydrogel to confer an immunomodulatory activity. In addition to the improvement in swelling and anti-degradation properties, the composite SIS hydrogel has attained satisfying free radical scavenging and sustained IL-10 release. Meanwhile, the hydrogel possessed excellent anti-oxidative and immunomodulatory abilities to promote the polarization of M2c macrophages, thereby regulating collagen synthesis and providing a favorable immune environment for angiogenesis and extracellular matrix remodeling. Above results have therefore provided a facile but effective strategy to improve the therapeutic effects of the SIS hydrogel and expand its scope of clinical applications.

Bioactive mineralized small intestinal submucosa acellular matrix/PMMA bone cement for vertebral bone regeneration.

Polymethylmethacrylate (PMMA) bone cement extensively utilized for the treatment of osteoporotic vertebral compression fractures due to its exceptional handleability and mechanical properties. Nevertheless, the clinical application of PMMA bone cement is restricted by its poor bioactivity and excessively high modulus of elasticity. Herein, mineralized small intestinal submucosa (mSIS) was incorporated into PMMA to prepare a partially degradable bone cement (mSIS-PMMA) that provided suitable compressive strength and reduced elastic modulus compared to pure PMMA. The ability of mSIS-PMMA bone cement to promote the attachment, proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells was shown through cellular experiments carried out in vitro, and an animal osteoporosis model validated its potential to improve osseointegration. Considering these benefits, mSIS-PMMA bone cement shows promising potential as an injectable biomaterial for orthopedic procedures that require bone augmentation.

Clinical outcomes of a novel porcine small intestinal submucosa patch for full-thickness hand skin defects: a retrospective investigation

ObjectiveTo investigate the clinical outcomes of a novel soft tissue repair patch (porcine small intestinal submucosa patch, SIS patch) in the treatment of full-thickness hand skin defects.MethodsFrom January 2017 to July 2019, 80 patients with hand soft tissue defects, who met the inclusion criteria, were retrospectively reviewed and divided into two groups. After debridement, patients in group A were treated with the novel SIS patch to cover the wound, and patients in group B were treated with autologous skin graft. The dimensions of skin defect area and healing outcome were evaluated and recorded. Scar assessment was carried out using Scar Cosmesis Assessment and Rating Scale (SCAR scale) at the last follow-up postoperation, and the recovery of wound sensation was assessed at the same time using British Medical Research Council (BMRC) grading of sensorimotor recovery. All the data were collected and statistically analyzed.ResultsA total of 80 patients were enrolled in the study with 40 patients in each group. Four patients in group A and 5 patients in group B were excluded due to wound infection and lost to follow-up. There were 36 patients in group A and 35 patients in group B finally got follow-up postoperation with mean interval of 12.75 ± 5.61 months in group A and 14.11 ± 5.42 months in group B. The dimensions of skin defect area in group A ranged from 7.5 to 87.5 cm2 (mean 25.97 ± 18.66 cm2) and in group B ranged from 7.5 to 86.25 cm2 (mean 33.61 ± 19.27 cm2) which have no significant difference (P > 0.05). SCAR scale results of group A and group B were 10.98 ± 0.33 and 9.49 ± 0.35, respectively, and the difference was statistically significant (P < 0.05). BMRC grading results showed 6 cases of S4, 11 cases of S3+, 5 cases of S3, 6 cases of S2, 6 cases of S1 and 2 cases of S0 in group A, and 8 cases of S4, 10 cases of S3+, 7 cases of S3, 4 cases of S2, 5 cases of S1, and 1 case of S0 in group B, which had no significant difference between them (P > 0.05).ConclusionsThe novel SIS patch is an applicable biological material in the treatment of hand skin defect, which could achieve a better cosmetic appearance of the newborn skin tissue.

SIS membrane modification to improve antimicrobial and osteogenic properties for guide bone regeneration

The guided bone regeneration (GBR) technique is the most common and durable approach to repairing bone defects in periodontal surgery. However, membrane exposure causes bacterial infiltration, which lowers the functional integrity of the barrier membrane and destroys bone repair. Here, an antibacterial peptide-modified small intestinal submucosa (SIS) membrane is used as a new GBR membrane for effective bone regeneration. The peptide JH8194 was placed into chitosan microspheres to preserve its stability and allow for sustained release, which realizes rapid and efficient functional modification of the SIS membrane. Biocompatibility and certain antibacterial activities were found in the modified SIS membrane (SIS@CS-JH8194). Additionally, in vitro experiments showed that SIS@CS-JH8194 promoted the expression of osteogenic-related factors and decreased the secretion of inflammatory factors in rat bone mesenchymal stem cells. In vivo experiments showed that SIS@CS-JH8194 could effectively promote bone regeneration in rat skull defects. In this work, we created a new antibacterial GBR membrane to help avoid postoperative infection and improve bone tissue regeneration.

Bionic artificial penile Tunica albuginea

Bionic artificial penile Tunica albuginea

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.

Decorated small intestinal submucosa (SIS) based bio-patch with anti-fouling and vascularized capacity to accelerate chronic wound regeneration via TGF-β and MAPK pathway

Chronic wounds in diabetes take a lifetime risk of developing into diabetic foot ulcers (DFUs). Conventional wound dressings and commercial products fail for ideal tissue regeneration in DFUs due to the incapacity to promote vascularization and prevent bacterial infections during wound repair. In this study, the small intestinal submucosa (SIS) with enriched vascularized bioactive factors, was chemically decorated by 2-methacryloyloxy ethyl phosphorylcholine (MPC) through Michael-type addition to be endowed anti-fouling ability, in order to treat chronic wound regeneration in diabetes. In the diabetic skin injury experiment, we established the animal model by 5-mm diameter defects in the SD rats and implanted the bio-patches to the located sites. The SIS-MPC bio-patch showed superior advantages in bacterial anti-adhesion (100-fold foul resistance than commercial patches), while maintained affinity for fibroblast growth and collagen formation, as demonstrated by immunohistochemical staining from the local tissues, outperforming commercial wound dressings in tissue regeneration, which was attributed to acceleration in neovascularization and inflammation modulation through TGF-β and MAPK pathway. This novel SIS-MPC bio-patch would be a promising candidate for medical translations into diabetes and chronic wound treatments.