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Stephen F. Badylak - One of the best experts on this subject based on the ideXlab platform.
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Extracellular Matrix Patches for Endarterectomy Repair.
Frontiers in cardiovascular medicine, 2021Co-Authors: Keith B. Allen, Stephen F. Badylak, Joshua D. Adams, H. Edward Garrett, Nicolas J. Mouawad, Steven W. Oweida, Manesh Parikshak, Parvez K. SultanAbstract:Patch repair is the preferred method for arteriotomy closure following femoral or carotid endarterectomy. Choosing among available patch options remains a clinical challenge, as current evidence suggests roughly comparable outcomes between autologous grafts and synthetic and biologic materials. Biologic patches have potential advantages over other materials, including reduced risk for infection, mitigation of an excessive foreign body response, and the potential to remodel into healthy, vascularized tissue. Here we review the use of decellularized extracellular matrix (ECM) for cardiovascular applications, particularly endarterectomy repair, and the capacity of these materials to remodel into native, site-appropriate tissues. Also presented are data from two post-market observational studies of patients undergoing iliofemoral and carotid endarterectomy patch repair as well as one histologic case report in a challenging iliofemoral endarterectomy repair, all with the use of small intestine submucosa (SIS)-ECM. In alignment with previously reported studies, high patency was maintained, and adverse event rates were comparable to previously reported rates of patch angioplasty. Histologic analysis from one case identified Constructive Remodeling of the SIS-ECM, consistent with the histologic characteristics of the endarterectomized vessel. These clinical and histologic results align with the biologic potential described in the academic ECM literature. To our knowledge, this is the first histologic demonstration of SIS-ECM Remodeling into site-appropriate vascular tissues following endarterectomy. Together, these findings support the safety and efficacy of SIS-ECM for patch repair of femoral and carotid arteriotomy.
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Extracellular Matrix Bioscaffolds for Building Gastrointestinal Tissue
Cellular and Molecular Gastroenterology and Hepatology, 2018Co-Authors: George S. Hussey, Madeline C. Cramer, Stephen F. BadylakAbstract:Regenerative medicine is a rapidly advancing field that uses principles of tissue engineering, developmental biology, stem cell biology, immunology, and bioengineering to reconstruct diseased or damaged tissues. Biologic scaffolds composed of extracellular matrix have shown great promise as an inductive substrate to facilitate the Constructive Remodeling of gastrointestinal (GI) tissue damaged by neoplasia, inflammatory bowel disease, and congenital or acquired defects. The present review summarizes the preparation and use of extracellular matrix scaffolds for bioengineering of the GI tract, identifies significant advances made in regenerative medicine for the reconstruction of functional GI tissue, and describes an emerging therapeutic approach.
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Biologic Scaffolds.
Cold Spring Harbor perspectives in medicine, 2017Co-Authors: Alessandra Costa, Ricardo Londono, Juan Diego Naranjo, Stephen F. BadylakAbstract:Biologic scaffold materials composed of allogeneic or xenogeneic extracellular matrix are commonly used for the repair and functional reconstruction of injured and missing tissues. These naturally occurring bioscaffolds are manufactured by the removal of the cellular content from source tissues while preserving the structural and functional molecular units of the remaining extracellular matrix (ECM). The mechanisms by which these bioscaffolds facilitate Constructive Remodeling and favorable clinical outcomes include release or creation of effector molecules that recruit endogenous stem/progenitor cells to the site of scaffold placement and modulation of the innate immune response, specifically the activation of an anti-inflammatory macrophage phenotype. The methods by which ECM biologic scaffolds are prepared, the current understanding of in vivo scaffold Remodeling, and the associated clinical outcomes are discussed in this article.
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Host Response to Implanted Materials and Devices: An Overview
The Immune Response to Implanted Materials and Devices, 2016Co-Authors: Michelle E. Scarritt, Ricardo Londono, Stephen F. BadylakAbstract:The host response to implanted materials and devices is influenced not only by the design of the material itself, but also by the local and systemic environment of the host. Much of the early response follows the well-described cascade of events of wound healing from hemostasis to scar formation. An implanted material can positively or negatively modulate this cascade of events, culminating in a Constructive Remodeling response, a persistent inflammatory response, a foreign body response with encapsulation, or an adaptive immune response. An overview of these events, as well as the influence of biologic versus synthetic materials, is discussed in this chapter.
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Solubilized extracellular matrix bioscaffolds derived from diverse source tissues differentially influence macrophage phenotype.
Journal of biomedical materials research. Part A, 2016Co-Authors: Jenna L. Dziki, Brian M Sicari, Derek S. Wang, Catalina Pineda, Theresa Rausch, Stephen F. BadylakAbstract:The host response to biomaterials is a critical determinant of their success or failure in tissue-repair applications. Macrophages are among the first responders in the host response to biomaterials and have been shown to be predictors of downstream tissue Remodeling events. Biomaterials composed of mammalian extracellular matrix (ECM) in particular have been shown to promote distinctive and Constructive Remodeling outcomes when compared to their synthetic counterparts, a property that has been largely attributed to their ability to modulate the host macrophage response. ECM bioscaffolds are prepared by decellularizing source tissues such as dermis and small intestinal submucosa. The differential ability of such scaffolds to influence macrophage behavior has not been determined. The present study determines the effects of ECM bioscaffolds derived from eight different source tissues upon macrophage surface marker expression, protein content, phagocytic capability, metabolism, and antimicrobial activity. The results show that macrophages exposed to small intestinal submucosa (SIS), urinary bladder matrix (UBM), brain ECM (bECM), esophageal ECM (eECM), and colonic ECM (coECM) express a predominant M2-like macrophage phenotype, which is pro-Remodeling and anti-inflammatory (iNOS-/Fizz1+/CD206+). In contrast, macrophage exposure to dermal ECM resulted in a predominant M1-like, pro-inflammatory phenotype (iNOS+/Fizz1-/CD206-), whereas liver ECM (LECM) and skeletal muscle ECM (mECM) did not significantly change the expression of these markers. All solubilized ECM bioscaffold treatments resulted in an increased macrophage antimicrobial activity, but no differences were evident in macrophage phagocytic capabilities, and macrophage metabolism was decreased following exposure to UBM, bECM, mECM, coECM, and dECM. The present work could have important implications when considering the macrophage response following ECM implantation for site-appropriate tissue Remodeling. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 138-147, 2017.
Thomas W. Gilbert - One of the best experts on this subject based on the ideXlab platform.
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Urinary Bladder Matrix Scaffolds Promote Pericardium Repair in a Porcine Model.
The Journal of surgical research, 2020Co-Authors: Natalia Amigo, Juan Martin Riganti, Mauricio Ramirez, Lorenzi Andrea, Pedro Renda, Romina Lovera, Ariel Pascaner, Carlos A. Vigliano, Damian Craiem, Thomas W. GilbertAbstract:Abstract Pericardium closure after cardiac surgery is recommended to prevent postoperative adhesions to the sternum. Synthetic materials have been used as substitutes, with limited results because of impaired Remodeling and fibrotic tissue formation. Urinary bladder matrix (UBM) scaffolds promote Constructive Remodeling that more closely resemble the native tissue. The aim of the study is to evaluate the host response to UBM scaffolds in a porcine model of partial pericardial resection. Twelve Landrace pigs were subjected to a median sternotomy. A 5 × 7 cm pericardial defect was created and then closed with a 5 × 7 cm multilayer UBM patch (UBM group) or left as an open defect (control group). Animals were survived for 8 wk. End points included gross morphology, biomechanical testing, histology with semiquantitative score, and cardiac function. The UBM group showed mild adhesions, whereas the control group showed fibrosis at the repair site, with robust adhesions and injury to the coronary bed. Load at failure (gr) and stiffness (gr/mm) were lower in the UBM group compared with the native pericardium (199.9 ± 59.2 versus 405.3 ± 99.89 g, P = 0.0536 and 44.23 ± 15.01 versus 146.5 ± 24.38 g/mm, P = 0.0025, respectively). In the UBM group, the histology resembled native pericardial tissue, with neovascularization, neofibroblasts, and little inflammatory signs. In contrast, control group showed fibrotic tissue with mononuclear infiltrates and a lack of organized collagen fibers validated with a histologic score. Both groups had normal ultrasonography results without cardiac motility disorders. In this setting, UBM scaffolds showed appropriate features for pericardial repair, restoring tissue properties that could help reduce postsurgical adhesions and prevent its associated complications.
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Reprint of: Extracellular matrix as a biological scaffold material: Structure and function
Acta Biomaterialia, 2015Co-Authors: Stephen F. Badylak, Donald O. Freytes, Thomas W. GilbertAbstract:Biological scaffold materials derived from the extracellular matrix (ECM) of intact mammalian tissues have been successfully used in a variety of tissue engineering/regenerative medicine applications both in preclinical studies and in clinical applications. Although it is recognized that the materials have Constructive Remodeling properties, the mechanisms by which functional tissue restoration is achieved are not well understood. There is evidence to support essential roles for both the structural and functional characteristics of the biological scaffold materials. This paper provides an overview of the composition and structure of selected ECM scaffold materials, the effects of manufacturing methods upon the structural properties and resulting mechanical behavior of the scaffold materials, and the in vivo degradation and Remodeling of ECM scaffolds with an emphasis on tissue function.
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Bone marrow-derived cells participate in the long-term Remodeling in a mouse model of esophageal reconstruction.
The Journal of surgical research, 2012Co-Authors: Alejandro Nieponice, Scott A. Johnson, Thomas W. Gilbert, Neill J Turner, Stephen F. BadylakAbstract:Abstract Background The default response of the esophagus to injury includes inflammation and scar tissue formation often leading to stricture. Biologic scaffolds composed of extracellular matrix (ECM) have been associated with the reconstitution of functional esophageal tissue in preclinical studies and clinical case reports of esophageal mucosal resection, anastomotic reinforcement, and full circumferential replacement. However, the mechanisms responsible for this change in the default response to esophageal injury are not fully understood. Methods The objective of the present study was to determine whether bone marrow–derived cells (BMCs) participate in the long-term Remodeling of ECM scaffolds in the esophageal location in a mouse model. Results BMCs were present in low numbers in Remodeling ECM scaffolds. Compared with the untreated control mice, the ECM-implanted animals showed better Remodeling of the epithelial layer. Conclusions BMCs are involved in ECM Remodeling process during tissue repair after esophageal injury, but the low numbers argue against any significant involvement in the Constructive Remodeling process.
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esophageal preservation in five male patients after endoscopic inner layer circumferential resection in the setting of superficial cancer a regenerative medicine approach with a biologic scaffold
Tissue Engineering Part A, 2011Co-Authors: Stephen F. Badylak, Thomas W. Gilbert, Toshitaka Hoppo, Alejandro Nieponice, Jon M Davison, Blair A JobeAbstract:As a result of injury caused by chronic gastroesophageal reflux, Barrett's esophagus with high-grade dysplasia and esophageal adenocarcinoma are rapidly increasing problems in the United States. The current standard of care involves esophagectomy, a procedure associated with a high morbidity, a negative impact on long term quality of life, and a mortality rate of 1–6 percent. An entirely endoscopic technique for circumferential, long segment en bloc removal of the mucosa and submucosa with subsequent placement of a biologic scaffold material that promotes a Constructive Remodeling response and minimizes stricture is described herein. The results of this approach are reported for five patients with 4–24-month follow-up. Restoration of normal mature, K4+/K14+, squamous epithelium, and return to a normal diet without significant dysphagia is reported for all patients. Two of five patients show a small focus of recurrent Barrett's esophagus at the gastroesophageal junction, but the entire length and circumfer...
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Constructive Remodeling of biologic scaffolds is dependent on early exposure to physiologic bladder filling in a canine partial cystectomy model
Journal of Surgical Research, 2010Co-Authors: Alan V Boruch, Thomas W. Gilbert, Alejandro Nieponice, Irfan Qureshi, Stephen F. BadylakAbstract:Biologic scaffolds composed of extracellular matrix (ECM) have been used to facilitate the Constructive Remodeling of several tissue types. Previous studies suggest that the ECM scaffold Remodeling process is dependent on microenvironmental factors, including tissue-specific biomechanical loading. The objective of the present study was to evaluate the effects of long-term catheterization (LTC), with its associated inhibition of bladder filling and physiologic biomechanical loading, on ECM scaffold Remodeling following partial cystectomy in a canine model. Reconstruction of the partial cystectomy site was performed using ECM scaffolds prepared from porcine small intestinal submucosa (SIS) or porcine urinary bladder matrix (UBM). Animals were randomly assigned to either a long-term catheterization (LTC) group (n = 5, catheterized 28 d) or a short-term catheterization group (STC, n = 5, catheterized 24h), and scaffold Remodeling was assessed by histologic methods at 4 and 12 wk postoperatively. By 4 wk, animals in the STC group showed a well-developed and highly differentiated urothelium, a robust vascularization network, abundant smooth muscle actin (SMA), and smooth muscle myosin heavy chain (smMHC) expressing spindle-shaped cells, and many neuronal processes associated with newly formed arterioles. In contrast, at 4 wk the scaffolds in LTC animals were not epithelialized, and did not express neuronal markers. The scaffolds in the LTC group developed a dense granulation tissue containing SMA+, smMHC–, spindle-shaped cells that were morphologically and phenotypically consistent with myofibroblasts, but not smooth muscle cells. By 12 wk postoperatively, the ECM scaffolds in the STC animals showed a Constructive Remodeling response, with a differentiated urothelium and islands of smooth muscle cells within the remodeled scaffold. In contrast, at 12 wk the scaffolds in LTC animals had a Remodeling response more consistent with fibrosis even though catheters had been removed 8 wk earlier. These findings show that early exposure of site-appropriate mechanical loading (i.e., bladder filling) mediates a Constructive Remodeling response after ECM repair in a canine partial cystectomy model.
Ricardo Londono - One of the best experts on this subject based on the ideXlab platform.
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Biologic Scaffolds.
Cold Spring Harbor perspectives in medicine, 2017Co-Authors: Alessandra Costa, Ricardo Londono, Juan Diego Naranjo, Stephen F. BadylakAbstract:Biologic scaffold materials composed of allogeneic or xenogeneic extracellular matrix are commonly used for the repair and functional reconstruction of injured and missing tissues. These naturally occurring bioscaffolds are manufactured by the removal of the cellular content from source tissues while preserving the structural and functional molecular units of the remaining extracellular matrix (ECM). The mechanisms by which these bioscaffolds facilitate Constructive Remodeling and favorable clinical outcomes include release or creation of effector molecules that recruit endogenous stem/progenitor cells to the site of scaffold placement and modulation of the innate immune response, specifically the activation of an anti-inflammatory macrophage phenotype. The methods by which ECM biologic scaffolds are prepared, the current understanding of in vivo scaffold Remodeling, and the associated clinical outcomes are discussed in this article.
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Host Response to Implanted Materials and Devices: An Overview
The Immune Response to Implanted Materials and Devices, 2016Co-Authors: Michelle E. Scarritt, Ricardo Londono, Stephen F. BadylakAbstract:The host response to implanted materials and devices is influenced not only by the design of the material itself, but also by the local and systemic environment of the host. Much of the early response follows the well-described cascade of events of wound healing from hemostasis to scar formation. An implanted material can positively or negatively modulate this cascade of events, culminating in a Constructive Remodeling response, a persistent inflammatory response, a foreign body response with encapsulation, or an adaptive immune response. An overview of these events, as well as the influence of biologic versus synthetic materials, is discussed in this chapter.
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inhibition of cox1 2 alters the host response and reduces ecm scaffold mediated Constructive tissue Remodeling in a rodent model of skeletal muscle injury
Acta Biomaterialia, 2016Co-Authors: Ricardo Londono, Timothy J Keane, Christopher L. Dearth, Peter F Slivka, Scott A Stewart, Francis X Pizza, Stephen F. BadylakAbstract:Abstract Extracellular matrix (ECM) has been used as a biologic scaffold material to both reinforce the surgical repair of soft tissue and serve as an inductive template to promote a Constructive tissue Remodeling response. Success of such an approach is dependent on macrophage-mediated degradation and Remodeling of the biologic scaffold. Macrophage phenotype during these processes is a predictive factor of the eventual Remodeling outcome. ECM scaffolds have been shown to promote an anti-inflammatory or M2-like macrophage phenotype in vitro that includes secretion of downstream products of cycolooxygenases 1 and 2 (COX1/2). The present study investigated the effect of a common COX1/2 inhibitor (Aspirin) on macrophage phenotype and tissue Remodeling in a rodent model of ECM scaffold treated skeletal muscle injury. Inhibition of COX1/2 reduced the Constructive Remodeling response by hindering myogenesis and collagen deposition in the defect area. The inhibited response was correlated with a reduction in M2-like macrophages in the defect area. The effects of Aspirin on macrophage phenotype were corroborated using an established in vitro macrophage model which showed a reduction in both ECM induced prostaglandin secretion and expression of a marker of M2-like macrophages (CD206). These results raise questions regarding the common peri-surgical administration of COX1/2 inhibitors when biologic scaffold materials are used to facilitate muscle repair/regeneration. Statement of significance COX1/2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely administered post-surgically for analgesic purposes. While COX1/2 inhibitors are important in pain management, they have also been shown to delay or diminish the healing process, which calls to question their clinical use for treating musculotendinous injuries. The present study aimed to investigate the influence of a common NSAID, Aspirin, on the Constructive Remodeling response mediated by an ECM scaffold (UBM) in a rat skeletal muscle injury model. The COX1/2 inhibitor, Aspirin, was found to mitigate the ECM scaffold-mediated Constructive Remodeling response both in an in vitro co-culture system and an in vivo rat model of skeletal muscle injury. The results presented herein provide data showing that NSAIDs may significantly alter tissue Remodeling outcomes when a biomaterial is used in a regenerative medicine/tissue engineering application. Thus, the decision to prescribe NSAIDs to manage the symptoms of inflammation post-ECM scaffold implantation should be carefully considered.
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Inhibition of COX1/2 alters the host response and reduces ECM scaffold mediated Constructive tissue Remodeling in a rodent model of skeletal muscle injury.
Acta biomaterialia, 2015Co-Authors: Christopher L. Dearth, Ricardo Londono, Timothy J Keane, Peter F Slivka, Scott A Stewart, Francis X Pizza, Justin K. Tay, Qingnian Goh, Stephen F. BadylakAbstract:Abstract Extracellular matrix (ECM) has been used as a biologic scaffold material to both reinforce the surgical repair of soft tissue and serve as an inductive template to promote a Constructive tissue Remodeling response. Success of such an approach is dependent on macrophage-mediated degradation and Remodeling of the biologic scaffold. Macrophage phenotype during these processes is a predictive factor of the eventual Remodeling outcome. ECM scaffolds have been shown to promote an anti-inflammatory or M2-like macrophage phenotype in vitro that includes secretion of downstream products of cycolooxygenases 1 and 2 (COX1/2). The present study investigated the effect of a common COX1/2 inhibitor (Aspirin) on macrophage phenotype and tissue Remodeling in a rodent model of ECM scaffold treated skeletal muscle injury. Inhibition of COX1/2 reduced the Constructive Remodeling response by hindering myogenesis and collagen deposition in the defect area. The inhibited response was correlated with a reduction in M2-like macrophages in the defect area. The effects of Aspirin on macrophage phenotype were corroborated using an established in vitro macrophage model which showed a reduction in both ECM induced prostaglandin secretion and expression of a marker of M2-like macrophages (CD206). These results raise questions regarding the common peri-surgical administration of COX1/2 inhibitors when biologic scaffold materials are used to facilitate muscle repair/regeneration. Statement of significance COX1/2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely administered post-surgically for analgesic purposes. While COX1/2 inhibitors are important in pain management, they have also been shown to delay or diminish the healing process, which calls to question their clinical use for treating musculotendinous injuries. The present study aimed to investigate the influence of a common NSAID, Aspirin, on the Constructive Remodeling response mediated by an ECM scaffold (UBM) in a rat skeletal muscle injury model. The COX1/2 inhibitor, Aspirin, was found to mitigate the ECM scaffold-mediated Constructive Remodeling response both in an in vitro co-culture system and an in vivo rat model of skeletal muscle injury. The results presented herein provide data showing that NSAIDs may significantly alter tissue Remodeling outcomes when a biomaterial is used in a regenerative medicine/tissue engineering application. Thus, the decision to prescribe NSAIDs to manage the symptoms of inflammation post-ECM scaffold implantation should be carefully considered.
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Biologic Scaffolds for Regenerative Medicine: Mechanisms of In vivo Remodeling
Annals of Biomedical Engineering, 2015Co-Authors: Ricardo Londono, Stephen F. BadylakAbstract:Successful regenerative medicine strategies for functional tissue reconstruction include the in situ placement of acellular materials composed of the extracellular matrix (ECM) or individual components of the ECM. The composition and ultrastructure of these materials vary depending on multiple factors including the tissue source and species from which the materials are harvested, the methods of manufacture, the efficiency of decellularization, post-processing modifications such as chemical cross-linking or solubilization, and the methods of terminal sterilization. Appropriately configured materials have the ability to modulate different stages of the healing response by inducing a shift from a process of inflammation and scar tissue formation to one of Constructive Remodeling and functional tissue restoration. The events that facilitate such a dramatic change during the biomaterial-host interaction are complex and necessarily involve both the immune system and mechanisms of stem cell recruitment, growth, and differentiation. The present manuscript reviews the composition of biologic scaffolds, the methods and recommendations for manufacture, the mechanisms of the biomaterial–host interaction, and the clinical application of this regenerative medicine approach.
Kathleen A. Derwin - One of the best experts on this subject based on the ideXlab platform.
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Characterization of and host response to tyramine substituted-hyaluronan enriched fascia extracellular matrix
Journal of Materials Science: Materials in Medicine, 2011Co-Authors: Likang Chin, Anthony Calabro, E. Rene Rodriguez, Carmela D. Tan, Esteban Walker, Kathleen A. DerwinAbstract:Naturally-occurring biomaterial scaffolds derived from extracellular matrix (ECM) have been previously investigated for soft tissue repair. We propose to enrich fascia ECM with high molecular weight tyramine substituted-hyaluronan (TS-HA) to modulate inflammation associated with implantation and enhance fibroblast infiltration. As critical determinants of Constructive Remodeling, the host inflammatory response and macrophage polarization to TS-HA enriched fascia were characterized in a rat abdominal wall model. TS-HA treated fascia with cross-linking had a similar lymphocyte ( P = 0.11) and plasma cell ( P = 0.13) densities, greater macrophage ( P = 0.001) and giant cell ( P
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Characterization of and host response to tyramine substituted-hyaluronan enriched fascia extracellular matrix.
Journal of materials science. Materials in medicine, 2011Co-Authors: Likang Chin, Anthony Calabro, E. Rene Rodriguez, Carmela D. Tan, Esteban Walker, Kathleen A. DerwinAbstract:Naturally-occurring biomaterial scaffolds derived from extracellular matrix (ECM) have been previously investigated for soft tissue repair. We propose to enrich fascia ECM with high molecular weight tyramine substituted-hyaluronan (TS-HA) to modulate inflammation associated with implantation and enhance fibroblast infiltration. As critical determinants of Constructive Remodeling, the host inflammatory response and macrophage polarization to TS-HA enriched fascia were characterized in a rat abdominal wall model. TS-HA treated fascia with cross-linking had a similar lymphocyte (P = 0.11) and plasma cell (P = 0.13) densities, greater macrophage (P = 0.001) and giant cell (P < 0.0001) densities, and a lower density of fibroblast-like cells (P < 0.0001) than water treated controls. Treated fascia, with or without cross-linking, exhibited a predominantly M2 pro-Remodeling macrophage profile similar to water controls (P = 0.82), which is suggestive of Constructive tissue Remodeling. Our findings demonstrated that HA augmentation can alter the host response to an ECM, but the appropriate concentration and molecular weight needed to minimize chronic inflammation within the scaffold remains to be determined.
Christopher L. Dearth - One of the best experts on this subject based on the ideXlab platform.
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inhibition of cox1 2 alters the host response and reduces ecm scaffold mediated Constructive tissue Remodeling in a rodent model of skeletal muscle injury
Acta Biomaterialia, 2016Co-Authors: Ricardo Londono, Timothy J Keane, Christopher L. Dearth, Peter F Slivka, Scott A Stewart, Francis X Pizza, Stephen F. BadylakAbstract:Abstract Extracellular matrix (ECM) has been used as a biologic scaffold material to both reinforce the surgical repair of soft tissue and serve as an inductive template to promote a Constructive tissue Remodeling response. Success of such an approach is dependent on macrophage-mediated degradation and Remodeling of the biologic scaffold. Macrophage phenotype during these processes is a predictive factor of the eventual Remodeling outcome. ECM scaffolds have been shown to promote an anti-inflammatory or M2-like macrophage phenotype in vitro that includes secretion of downstream products of cycolooxygenases 1 and 2 (COX1/2). The present study investigated the effect of a common COX1/2 inhibitor (Aspirin) on macrophage phenotype and tissue Remodeling in a rodent model of ECM scaffold treated skeletal muscle injury. Inhibition of COX1/2 reduced the Constructive Remodeling response by hindering myogenesis and collagen deposition in the defect area. The inhibited response was correlated with a reduction in M2-like macrophages in the defect area. The effects of Aspirin on macrophage phenotype were corroborated using an established in vitro macrophage model which showed a reduction in both ECM induced prostaglandin secretion and expression of a marker of M2-like macrophages (CD206). These results raise questions regarding the common peri-surgical administration of COX1/2 inhibitors when biologic scaffold materials are used to facilitate muscle repair/regeneration. Statement of significance COX1/2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely administered post-surgically for analgesic purposes. While COX1/2 inhibitors are important in pain management, they have also been shown to delay or diminish the healing process, which calls to question their clinical use for treating musculotendinous injuries. The present study aimed to investigate the influence of a common NSAID, Aspirin, on the Constructive Remodeling response mediated by an ECM scaffold (UBM) in a rat skeletal muscle injury model. The COX1/2 inhibitor, Aspirin, was found to mitigate the ECM scaffold-mediated Constructive Remodeling response both in an in vitro co-culture system and an in vivo rat model of skeletal muscle injury. The results presented herein provide data showing that NSAIDs may significantly alter tissue Remodeling outcomes when a biomaterial is used in a regenerative medicine/tissue engineering application. Thus, the decision to prescribe NSAIDs to manage the symptoms of inflammation post-ECM scaffold implantation should be carefully considered.
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Inhibition of COX1/2 alters the host response and reduces ECM scaffold mediated Constructive tissue Remodeling in a rodent model of skeletal muscle injury.
Acta biomaterialia, 2015Co-Authors: Christopher L. Dearth, Ricardo Londono, Timothy J Keane, Peter F Slivka, Scott A Stewart, Francis X Pizza, Justin K. Tay, Qingnian Goh, Stephen F. BadylakAbstract:Abstract Extracellular matrix (ECM) has been used as a biologic scaffold material to both reinforce the surgical repair of soft tissue and serve as an inductive template to promote a Constructive tissue Remodeling response. Success of such an approach is dependent on macrophage-mediated degradation and Remodeling of the biologic scaffold. Macrophage phenotype during these processes is a predictive factor of the eventual Remodeling outcome. ECM scaffolds have been shown to promote an anti-inflammatory or M2-like macrophage phenotype in vitro that includes secretion of downstream products of cycolooxygenases 1 and 2 (COX1/2). The present study investigated the effect of a common COX1/2 inhibitor (Aspirin) on macrophage phenotype and tissue Remodeling in a rodent model of ECM scaffold treated skeletal muscle injury. Inhibition of COX1/2 reduced the Constructive Remodeling response by hindering myogenesis and collagen deposition in the defect area. The inhibited response was correlated with a reduction in M2-like macrophages in the defect area. The effects of Aspirin on macrophage phenotype were corroborated using an established in vitro macrophage model which showed a reduction in both ECM induced prostaglandin secretion and expression of a marker of M2-like macrophages (CD206). These results raise questions regarding the common peri-surgical administration of COX1/2 inhibitors when biologic scaffold materials are used to facilitate muscle repair/regeneration. Statement of significance COX1/2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely administered post-surgically for analgesic purposes. While COX1/2 inhibitors are important in pain management, they have also been shown to delay or diminish the healing process, which calls to question their clinical use for treating musculotendinous injuries. The present study aimed to investigate the influence of a common NSAID, Aspirin, on the Constructive Remodeling response mediated by an ECM scaffold (UBM) in a rat skeletal muscle injury model. The COX1/2 inhibitor, Aspirin, was found to mitigate the ECM scaffold-mediated Constructive Remodeling response both in an in vitro co-culture system and an in vivo rat model of skeletal muscle injury. The results presented herein provide data showing that NSAIDs may significantly alter tissue Remodeling outcomes when a biomaterial is used in a regenerative medicine/tissue engineering application. Thus, the decision to prescribe NSAIDs to manage the symptoms of inflammation post-ECM scaffold implantation should be carefully considered.
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targeted rehabilitation after extracellular matrix scaffold transplantation for the treatment of volumetric muscle loss
American Journal of Physical Medicine & Rehabilitation, 2014Co-Authors: Natalie E Gentile, Christopher L. Dearth, Peter J Rubin, Fabrisia Ambrosio, Michael L Boninger, Kristen M Stearns, Elke H P Brown, Stephen F. BadylakAbstract:Rehabilitation therapy is an important aspect of recovery after volumetric muscle loss. However, the traditional rehabilitation approach involves a period of rest and passive loading followed by gradual active loading. Extracellular matrix is a naturally occurring material consisting of structural proteins that provide mechanical strength, structural support, and functional molecules with diverse bioactive properties. There is evidence to suggest that the addition of aggressive regenerative rehabilitation protocols immediately after surgical implantation of an extracellular matrix scaffold to an area of volumetric muscle loss has significant benefits for extracellular matrix Remodeling. Rehabilitation exercises likely provide the needed mechanical signals to encourage cell migration and site-specific differentiation in the temporal framework required for Constructive Remodeling. Herein, the authors review the literature and present an example of an aggressive rehabilitation program implemented immediately after extracellular matrix transplantation into a severely injured quadriceps muscle.
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an acellular biologic scaffold promotes skeletal muscle formation in mice and humans with volumetric muscle loss
Science Translational Medicine, 2014Co-Authors: Brian M Sicari, Neill J Turner, Matthew T. Wolf, Christopher L. Dearth, Peter J Rubin, Fabrisia Ambrosio, Michael L Boninger, Douglas J Weber, Tyler Simpson, Aaron WyseAbstract:Biologic scaffolds composed of naturally occurring extracellular matrix (ECM) can provide a microenvironmental niche that alters the default healing response toward a Constructive and functional outcome. The present study showed similarities in the Remodeling characteristics of xenogeneic ECM scaffolds when used as a surgical treatment for volumetric muscle loss in both a preclinical rodent model and five male patients. Porcine urinary bladder ECM scaffold implantation was associated with perivascular stem cell mobilization and accumulation within the site of injury, and de novo formation of skeletal muscle cells. The ECM-mediated Constructive Remodeling was associated with stimulus-responsive skeletal muscle in rodents and functional improvement in three of the five human patients.
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Human NELL1 Protein Augments Constructive Tissue Remodeling with Biologic Scaffolds
Cells tissues organs, 2013Co-Authors: Neill J Turner, Ricardo Londono, Christopher L. Dearth, Cymbeline T Culiat, Stephen F. BadylakAbstract:Biologic scaffolds composed of extracellular matrix (ECM) derived from decellularized tissues effectively reprogram key stages of the mammalian response to injury, altering the wound microenvironment from one that promotes scar tissue formation to one that stimulates Constructive and functional tissue Remodeling. In contrast, engineered scaffolds, composed of purified ECM components such as collagen, lack the complex ultrastructure and composition of intact ECM and may promote wound healing but lack factors that facilitate Constructive and functional tissue Remodeling. The objective of the present study was to test the hypothesis that addition of NELL1, a signaling protein that controls cell growth and differentiation, enhances the Constructive tissue Remodeling of a purified collagen scaffold. An abdominal wall defect model in the rat of 1.5-cm(2) partial thickness was used to compare the Constructive Remodeling of a bovine type I collagen scaffold to a biologic scaffold derived from small intestinal submucosa (SIS)-ECM with and without augmentation with 17 μg NELL1 protein. Samples were evaluated histologically at 14 days and 4 months. The contractile response of the defect site was also evaluated at 4 months. Addition of NELL1 protein improved the Constructive Remodeling of collagen scaffolds but not SIS-ECM scaffolds. Results showed an increase in the contractile force of the remodeled skeletal muscle and a fast:slow muscle composition similar to native tissue in the collagen-treated group. The already robust Remodeling response to SIS-ECM was not enhanced by NELL1 at the dose tested. These findings suggest that NELL1 protein does contribute to the enhanced Constructive Remodeling of skeletal muscle.