Unraveling the complex relationship between mRNA and protein abundances: a machine learning-based approach for imputing protein levels from RNA-seq data.

The correlation between messenger RNA (mRNA) and protein abundances has long been debated. RNA sequencing (RNA-seq), a high-throughput, commonly used method for analyzing transcriptional dynamics, leaves questions about whether we can translate RNA-seq-identified gene signatures directly to protein changes. In this study, we utilized a set of 17 widely assessed immune and wound healing mediators in the context of canine volumetric muscle loss to investigate the correlation of mRNA and protein abundances. Our data reveal an overall agreement between mRNA and protein levels on these 17 mediators when examining samples from the same experimental condition (e.g. the same biopsy). However, we observed a lack of correlation between mRNA and protein levels for individual genes under different conditions, underscoring the challenges in converting transcriptional changes into protein changes. To address this discrepancy, we developed a machine learning model to predict protein abundances from RNA-seq data, achieving high accuracy. Our approach also effectively corrected multiple extreme outliers measured by antibody-based protein assays. Additionally, this model has the potential to detect post-translational modification events, as shown by accurately estimating activated transforming growth factor ß1 levels. This study presents a promising approach for converting RNA-seq data into protein abundance and its biological significance.

3D Bioprinted Patient-Specific Extracellular Matrix Scaffolds for Soft Tissue Defects.

Soft tissue injuries such as volumetric muscle loss (VML) are often too large to heal normally on their own, resulting in scar formation and functional deficits. Decellularized extracellular matrix (dECM) scaffolds placed into these wounds have shown the ability to modulate the immune response and drive constructive healing. This provides a potential solution for functional tissue regeneration, however, these acellular dECM scaffolds are challenging to fabricate into complex geometries. 3D bioprinting is uniquely positioned to address this, being able to create patient-specific scaffolds based on clinical 3D imaging data. Here, a process to use freeform reversible embedding of suspended hydrogels (FRESH) 3D bioprinting and computed tomography (CT) imaging to build large volume, patient-specific dECM patches (≈12 × 8 × 2 cm) for implantation into canine VML wound models is developed. Quantitative analysis shows that these dECM patches are dimensionally accurate and conformally adapt to the surface of complex wounds. Finally, this approach is extended to a human VML injury to demonstrate the fabrication of clinically relevant dECM scaffolds with precise control over fiber alignment and micro-architecture. Together these advancements represent a step towards an improved, clinically translatable, patient-specific treatment for soft tissue defects from trauma, tumor resection, and other surgical procedures.

Transcriptomic, Proteomic, and Morphologic Characterization of Healing in Volumetric Muscle Loss.

Skeletal muscle has a robust, inherent ability to regenerate in response to injury from acute to chronic. In severe trauma, however, complete regeneration is not possible, resulting in a permanent loss of skeletal muscle tissue referred to as volumetric muscle loss (VML). There are few consistently reliable therapeutic or surgical options to address VML. A major limitation in investigation of possible therapies is the absence of a well-characterized large animal model. In this study, we present results of a comprehensive transcriptomic, proteomic, and morphologic characterization of wound healing following VML in a novel canine model of VML which we compare to a nine-patient cohort of combat-associated VML. The canine model is translationally relevant as it provides both a regional (spatial) and temporal map of the wound healing processes that occur in human VML. Collectively, these data show the spatiotemporal transcriptomic, proteomic, and morphologic properties of canine VML healing as a framework and model system applicable to future studies investigating novel therapies for human VML. Impact Statement The spatiotemporal transcriptomic, proteomic, and morphologic properties of canine volumetric muscle loss (VML) healing is a translational framework and model system applicable to future studies investigating novel therapies for human VML.

Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis.

Cathepsin K (Cat K) is a cysteine protease involved in bone remodeling. In addition to its role in bone biology, Cat K is upregulated in osteoclasts, chondrocytes and synoviocytes in osteoarthritic (OA) disease states making it a potential therapeutic target for disease-modifying OA. Starting from a prior preclinical compound, MK-1256, lead optimization efforts were carried out in the search for potent Cat K inhibitors with improved selectivity profiles with an emphasis on cathepsin F. Herein, we report the SAR studies which led to the discovery of the highly selective oxazole compound 23, which was subsequently shown to inhibit cathepsin K in vivo as measured by reduced levels of urinary C-telopeptide of collagen type I in dog.

Habitat selection in a recovering bobcat (Lynx rufus) population.

Understanding habitat selection of top predators is critical to predict their impacts on ecological communities and interactions with humans, particularly in recovering populations. We analyzed habitat selection in a recovering population of bobcats (Lynx rufus) in south-central Indiana using a Random Forest model. We predicted that bobcats would select forest habitat and forest edges but avoid agriculture to maximize encounters with prey species. We also predicted that bobcats would avoid developed areas and roads to minimize potential antagonistic interactions with humans. Results partially supported our predictions and were consistent with bobcats in the early stages of population expansion. Bobcats exhibited elevated use near forest edges, thresholds of avoidance near agriculture, and thresholds of selection for low and intermediate habitat heterogeneity. Bobcats exhibited peak probability of use 1-3 km from major roads, >800 m from minor roads, and <1km from developed areas, suggesting tradeoffs in reward for high-quality hunting areas and mortality risk. Our Random Forest model highlighted complex non-linear patterns and revealed that most shifts in habitat use occurred within 1 km of the edge of each habitat type. These results largely supported previous studies in the Midwest and across North America but also produced refinements of bobcat habitat use in our system, particularly at habitat boundaries. Refined models of habitat selection by carnivores enable improved prediction of the most suitable habitat for recovering populations and provides useful information for conservation.

Discovery and characterization of novel peptide inhibitors of the NRF2/MAFG/DNA ternary complex for the treatment of cancer.

Pathway activating mutations of the transcription factor NRF2 and its negative regulator KEAP1 are strongly correlative with poor clinical outcome with pemetrexed/carbo(cis)platin/pembrolizumab (PCP) chemo-immunotherapy in lung cancer. Despite the strong genetic support and therapeutic potential for a NRF2 transcriptional inhibitor, currently there are no known direct inhibitors of the NRF2 protein or its complexes with MAF and/or DNA. Herein we describe the design of a novel and high-confidence homology model to guide a medicinal chemistry effort that resulted in the discovery of a series of peptides that demonstrate high affinity, selective binding to the Antioxidant Response Element (ARE) DNA and thereby displace NRF2-MAFG from its promoter, which is an inhibitory mechanism that to our knowledge has not been previously described. In addition to their activity in electrophoretic mobility shift (EMSA) and TR-FRET-based assays, we show significant dose-dependent ternary complex disruption of NRF2-MAFG binding to DNA by SPR, as well as cellular target engagement by thermal destabilization of HiBiT-tagged NRF2 in the NCI-H1944 NSCLC cell line upon digitonin permeabilization, and SAR studies leading to improved cellular stability. We report the characterization and unique profile of lead peptide 18, which we believe to be a useful in vitro tool to probe NRF2 biology in cancer cell lines and models, while also serving as an excellent starting point for additional in vivo optimization toward inhibition of NRF2-driven transcription to address a significant unmet medical need in non-small cell lung cancer (NSCLC).

Identification of potent inhibitors of the sortilin-progranulin interaction.

High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.

A Systematic Review of Essential Oils and the Endocannabinoid System: A Connection Worthy of Further Exploration.

Aromatic compounds have a long history of use as medicines in most recorded cultures. An increasing interest in these therapeutic volatile molecules in both scientific and lay communities has led to the advancement of essential oils as phytomedicines. Recent discoveries suggest essential oils augment the endocannabinoid system in a positive manner to mitigate various pathologies. However, the exact mechanisms whereby essential oils influence endocannabinoid system activity are not fully known, these studies provide a glimpse into their involvement and warrant further evaluation. Additional study of the interaction between essential oils and the endocannabinoid system may lead to promising phytomedicines for the treatment of diseases and conditions involving dysregulation or activation of the endocannabinoid system.

Host macrophage response to injectable hydrogels derived from ECM and α-helical peptides.

Tissue engineering materials play a key role in how closely the complex architectural and functional characteristics of native healthy tissue can be replicated. Traditional natural and synthetic materials are superseded by bespoke materials that cross the boundary between these two categories. Here we present hydrogels that are derived from decellularised extracellular matrix and those that are synthesised from de novo α-helical peptides. We assess in vitro activation of murine macrophages to our hydrogels and whether these gels induce an M1-like or M2-like phenotype. This was followed by the in vivo immune macrophage response to hydrogels injected into rat partial-thickness abdominal wall defects. Over 28 days we observe an increase in mononuclear cell infiltration at the hydrogel-tissue interface without promoting a foreign body reaction and see no evidence of hydrogel encapsulation or formation of multinucleate giant cells. We also note an upregulation of myogenic differentiation markers and the expression of anti-inflammatory markers Arginase1, IL-10, and CD206, indicating pro-remodelling for all injected hydrogels. Furthermore, all hydrogels promote an anti-inflammatory environment after an initial spike in the pro-inflammatory phenotype. No difference between the injected site and the healthy tissue is observed after 28 days, indicating full integration. These materials offer great potential for future applications in regenerative medicine and towards unmet clinical needs. STATEMENT OF SIGNIFICANCE: Materials play a key role in how closely the complex architectural and functional characteristics of native healthy tissue can be replicated in tissue engineering. Here we present injectable hydrogels derived from decellularised extracellular matrix and de novo designed α-helical peptides. Over 28 days in the rat abdominal wall we observe an increase in mononuclear cell infiltration at the hydrogel-tissue interface with no foreign body reaction, no evidence of hydrogel encapsulation and no multinucleate giant cells. Our data indicate pro-remodelling and the promotion of an anti-inflammatory environment for all injected hydrogels with evidence of full integration with healthy tissue after 28 days. These unique materials offer great potential for future applications in regenerative medicine and towards designing materials for unmet clinical needs.

Multiple Synthetic Routes to the Mini-Protein Omomyc and Coiled-Coil Domain Truncations.

The Myc transcription factor represents an "undruggable" target of high biological interest due to its central role in various cancers. An abbreviated form of the c-Myc protein, called Omomyc, consists of the Myc DNA-binding domain and a coiled-coil region to facilitate dimerization of the 90 amino acid polypeptide. Here we present our results to evaluate the synthesis of Omomyc using three complementary strategies: linear Fmoc solid-phase peptide synthesis (SPPS) using several advancements for difficult sequences, native chemical ligation from smaller peptide fragments, and a high-throughput bacterial expression and assay platform for rapid mutagenesis. This multifaceted approach allowed access to up to gram quantities of the mini-protein and permitted in vitro and in vivo SAR exploration of this modality. DNA-binding results and cellular activity confirm that Omomyc and analogues presented here, are potent binders of the E-box DNA engaged by Myc for transcriptional activation and that this 90-amino acid mini-protein is cell permeable and can inhibit proliferation of Myc-dependent cell lines. We also present additional results on covalent homodimerization through disulfide formation of the full-length mini-protein and show the coiled-coil region can be truncated while preserving both DNA binding and cellular activity. Altogether, our results highlight the ability of advanced peptide synthesis to achieve SAR tractability in a challenging synthetic modality.

Strategy for Extending Half-life in Drug Design and Its Significance.

Preclinical optimization of compounds toward viable drug candidates requires an integrated understanding of properties that impact predictions of the clinically efficacious dose. The importance of optimizing half-life, unbound clearance, and potency and how they impact dose predictions are discussed in this letter. Modest half-life improvements for short half-life compounds can dramatically lower the efficacious dose. The relationship between dose and half-life is nonlinear when unbound clearance is kept constant, whereas the relationship between dose and unbound clearance is linear when half-life is kept constant. Due to this difference, we show that dose is more sensitive to changes in half-life than changes in unbound clearance when half-lives are shorter than 2 h. Through matched molecular pair analyses, we also show that the strategic introduction of halogens is likely to increase half-life and lower projected human dose even though increased lipophilicity does not guarantee extended half-life.

Sutureless nerve repair with ECM bioscaffolds and laser-activated chitosan adhesive.

The outcome of peripheral nerve repair following transection is influenced by a number of factors but almost all approaches require anastomosis of the nerve using technically demanding microsurgical procedures. However, the use of sutures presents a number of unavoidable challenges including additional nerve trauma, stimulation of an inflammatory response, and endoneural fibrosis. The objective of the present study was to determine the efficacy of a sutureless approach to nerve repair. A rat sciatic nerve transection model was used with a laser-activated, chitosan-based adhesive (SurgiLux), combined with different forms of extracellular matrix (ECM), known to promote Schwann cell proliferation and nerve growth both in peripheral nerve applications. Following a 5 mm transection of the sciatic nerve, nerve guide wraps were prepared using: (1) laser-activated adhesive (SurgiLux) alone, (2) SurgiLux incorporating ECM (SurgiLux ECM), (3) ECM secured using SurgiLux, and (4) ECM secured using 8-0 Prolene sutures. A no treatment groups was used as a negative control. Evaluation of tissue remodeling was conducted with histolomorphometric assessment of neuroma, integrity of repair, nerve immunolabeling, ratio of myelinated to non-myelinated fibers, and amount of connective tissue. Quantitative and semi-quantitative analysis of the repaired nerve transections at 6 and 12 weeks showed that that SurgiLux incorporating powdered ECM (SurgiLux ECM), SurgiLux alone and ECM alone all improved the healing response compared to no-treatment controls, with less fibrotic tissue and more nerve staining. Histologic scoring showed that the SurgiLux ECM group showed the greatest increase in histologic score between the two time points tested. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1698-1711, 2018.

Data to Decisions: Creating a Culture of Model-Driven Drug Discovery.

Merck & Co., Inc., Kenilworth, NJ, USA, is undergoing a transformation in the way that it prosecutes R&D programs. Through the adoption of a "model-driven" culture, enhanced R&D productivity is anticipated, both in the form of decreased attrition at each stage of the process and by providing a rational framework for understanding and learning from the data generated along the way. This new approach focuses on the concept of a "Design Cycle" that makes use of all the data possible, internally and externally, to drive decision-making. These data can take the form of bioactivity, 3D structures, genomics, pathway, PK/PD, safety data, etc. Synthesis of high-quality data into models utilizing both well-established and cutting-edge methods has been shown to yield high confidence predictions to prioritize decision-making and efficiently reposition resources within R&D. The goal is to design an adaptive research operating plan that uses both modeled data and experiments, rather than just testing, to drive project decision-making. To support this emerging culture, an ambitious information management (IT) program has been initiated to implement a harmonized platform to facilitate the construction of cross-domain workflows to enable data-driven decision-making and the construction and validation of predictive models. These goals are achieved through depositing model-ready data, agile persona-driven access to data, a unified cross-domain predictive model lifecycle management platform, and support for flexible scientist-developed workflows that simplify data manipulation and consume model services. The end-to-end nature of the platform, in turn, not only supports but also drives the culture change by enabling scientists to apply predictive sciences throughout their work and over the lifetime of a project. This shift in mindset for both scientists and IT was driven by an early impactful demonstration of the potential benefits of the platform, in which expert-level early discovery predictive models were made available from familiar desktop tools, such as ChemDraw. This was built using a workflow-driven service-oriented architecture (SOA) on top of the rigorous registration of all underlying model entities.

Perivascular extracellular matrix hydrogels mimic native matrix microarchitecture and promote angiogenesis via basic fibroblast growth factor.

Extracellular matrix (ECM)-derived bioscaffolds have been shown to elicit tissue repair through retention of bioactive signals. Given that the adventitia of large blood vessels is a richly vascularized microenvironment, we hypothesized that perivascular ECM contains bioactive signals that influence cells of blood vessel lineages. ECM bioscaffolds were derived from decellularized human and porcine aortic adventitia (hAdv and pAdv, respectively) and then shown have minimal DNA content and retain elastin and collagen proteins. Hydrogel formulations of hAdv and pAdv ECM bioscaffolds exhibited gelation kinetics similar to ECM hydrogels derived from porcine small intestinal submucosa (pSIS). hAdv and pAdv ECM hydrogels displayed thinner, less undulated, and fibrous microarchitecture reminiscent of native adventitia, with slight differences in ultrastructure visible in comparison to pSIS ECM hydrogels. Pepsin-digested pAdv and pSIS ECM bioscaffolds increased proliferation of human adventitia-derived endothelial cells and this effect was mediated in part by basic fibroblast growth factor (FGF2). Human endothelial cells cultured on Matrigel substrates formed more numerous and longer tube-like structures when supplemented with pAdv ECM bioscaffolds, and FGF2 mediated this matrix signaling. ECM bioscaffolds derived from pAdv promoted FGF2-dependent in vivo angiogenesis in the chick chorioallantoic membrane model. Using an angiogenesis-focused protein array, we detected 55 angiogenesis-related proteins, including FGF2 in hAdv, pAdv and pSIS ECMs. Interestingly, 19 of these factors were less abundant in ECMs bioscaffolds derived from aneurysmal specimens of human aorta when compared with non-aneurysmal (normal) specimens. This study reveals that Adv ECM hydrogels recapitulate matrix fiber microarchitecture of native adventitia, and retain angiogenesis-related actors and bioactive properties such as FGF2 signaling capable of influencing processes important for angiogenesis. This work supports the use of Adv ECM bioscaffolds for both discovery biology and potential translation towards microvascular regeneration in clinical applications.

The evolution of drug design at Merck Research Laboratories.

On October 5, 1981, Fortune magazine published a cover article entitled the "Next Industrial Revolution: Designing Drugs by Computer at Merck". With a 40+ year investment, we have been in the drug design business longer than most. During its history, the Merck drug design group has had several names, but it has always been in the "design" business, with the ultimate goal to provide an actionable hypothesis that could be tested experimentally. Often the result was a small molecule but it could just as easily be a peptide, biologic, predictive model, reaction, process, etc. To this end, the concept of design is now front and center in all aspects of discovery, safety assessment and early clinical development. At present, the Merck design group includes computational chemistry, protein structure determination, and cheminformatics. By bringing these groups together under one umbrella, we were able to align activities and capabilities across multiple research sites and departments. This alignment from 2010 to 2016 resulted in an 80% expansion in the size of the department, reflecting the increase in impact due to a significant emphasis across the organization to "design first" along the entire drug discovery path from lead identification (LID) to first in human (FIH) dosing. One of the major advantages of this alignment has been the ability to access all of the data and create an adaptive approach to the overall LID to FIH pathway for any modality, significantly increasing the quality of candidates and their probability of success. In this perspective, we will discuss how we crafted a new strategy, defined the appropriate phenotype for group members, developed the right skillsets, and identified metrics for success in order to drive continuous improvement. We will not focus on the tactical implementation, only giving specific examples as appropriate.

Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4.

G-protein-coupled receptor (GPCR) kinases (GRKs) bind to and phosphorylate GPCRs, initiating the process of GPCR desensitization and internalization. GRK4 is implicated in the regulation of blood pressure, and three GRK4 polymorphisms (R65L, A142V, and A486V) are associated with hypertension. Here, we describe the 2.6 Å structure of human GRK4α A486V crystallized in the presence of 5'-adenylyl ß,γ-imidodiphosphate. The structure of GRK4α is similar to other GRKs, although slight differences exist within the RGS homology (RH) bundle subdomain, substrate-binding site, and kinase C-tail. The RH bundle subdomain and kinase C-terminal lobe form a strikingly acidic surface, whereas the kinase N-terminal lobe and RH terminal subdomain surfaces are much more basic. In this respect, GRK4α is more similar to GRK2 than GRK6. A fully ordered kinase C-tail reveals interactions linking the C-tail with important determinants of kinase activity, including the αB helix, αD helix, and the P-loop. Autophosphorylation of wild-type GRK4α is required for full kinase activity, as indicated by a lag in phosphorylation of a peptide from the dopamine D1 receptor without ATP preincubation. In contrast, this lag is not observed in GRK4α A486V. Phosphopeptide mapping by mass spectrometry indicates an increased rate of autophosphorylation of a number of residues in GRK4α A486V relative to wild-type GRK4α, including Ser-485 in the kinase C-tail.

Understanding the role of alcohol during rape: the perfect storm of attention, emotion, & expectancies.

Sex offenders and violent offenders in general that were intoxicated at the time of their offense often claim that they were too intoxicated to know 1) what they were doing at the time of the offense and 2) therefore unable to recall the details of the offense situation the next day. What the literature has to say contradicts the claims of sex offenders or violent offenders who claim they were "out of control" and that they do not recall what they did in the offense situation. Alcohol use (mild to moderate consumption) appears to result in 1) alcohol myopia; 2) increased attentional focus on the more salient emotions (whether negative or positive); 3) improved creative thinking and improved attention to the activity at hand; 4) decreased frontal lobe activity (e.g., lack of concern about consequences or morals); 5) is impacted by alcohol expectancies; and 6) does not prevent an individual from being able to recall activity that occurred while intoxicated when provided cues.

In vivo degradation of 14C-labeled porcine dermis biologic scaffold.

Biologic scaffold materials are used for repair and reconstruction of injured or missing tissues. Such materials are often composed of allogeneic or xenogeneic extracellular matrix (ECM) manufactured by decellularization of source tissue, such as dermis. Dermal ECM (D-ECM) has been observed to degrade and remodel in vivo more slowly than other biologic scaffold materials, such as small intestinal submucosa (SIS-ECM). Histologic examination is a common method for evaluating material degradation, but it lacks sensitivity and is subject to observer bias. Utilization of (14)C-proline labeled ECM is a quantitative alternative for measuring degradation of ECM scaffolds. Using both methods, the amount of degradation of D-ECM and SIS-ECM was determined at 2, 4, and 24 weeks post-implantation in a rodent model. Results utilizing (14)C liquid scintillation counting (LSC) analysis showed distinct differences in degradation at the three time points. D-ECM material in situ stayed the same at 76% remaining from 2 to 4 weeks post-implantation, and then decreased to 44% remaining at 24 weeks. In the same time period, implanted SIS-ECM material decreased from 72% to 13% to 0%. Visual examination of device degradation by histology overestimated degradation at 2 weeks and underestimated device degradation at 24 weeks, compared to the (14)C method.

Role of the extracellular matrix in whole organ engineering.

End-stage organ failure is a devastating problem with limited therapeutic options. The definitive treatment is orthotropic transplantation, however, there exists a severe shortage of viable donor organs, and this shortage is worsening with an aging demographic and as the number of new cases of organ failure increases. Patients fortunate enough to receive a transplant are required to receive immunosuppressive therapies and can face transplant rejection. The emerging concept of organ engineering may offer a new hope for these patients. Researchers in the field of regenerative medicine and tissue engineering are using three-dimensional whole organ scaffolds composed of allogeneic or xenogeneic extracellular matrix (ECM) for engineering functional tissue suitable for transplantation. Perfusion decellularization is an approach that generates native ECM scaffolds with intact 3D anatomical architecture and vasculature. Decellularized organs provide the ideal transplantable scaffold with all the necessary microstructure and extracellular cues for cell attachment, differentiation, vascularization, and function. The present manuscript will review the role of the ECM in normal development, the concept of ECM tissue specificity, and the effect of processing methods on eventual clinical outcomes. An overview of existing challenges and future directions will also be discussed.

Polypropylene surgical mesh coated with extracellular matrix mitigates the host foreign body response.

Surgical mesh devices composed of synthetic materials are commonly used for ventral hernia repair. These materials provide robust mechanical strength and are quickly incorporated into host tissue; factors that contribute to reduced hernia recurrence rates. However, such mesh devices cause a foreign body response with the associated complications of fibrosis and patient discomfort. In contrast, surgical mesh devices composed of naturally occurring extracellular matrix (ECM) are associated with constructive tissue remodeling, but lack the mechanical strength of synthetic materials. A method for applying a porcine dermal ECM hydrogel coating to a polypropylene mesh is described herein with the associated effects upon the host tissue response and biaxial mechanical behavior. Uncoated and ECM coated heavy-weight BARD™ Mesh were compared to the light-weight ULTRAPRO™ and BARD™ Soft Mesh devices in a rat partial thickness abdominal defect overlay model. The ECM coated mesh attenuated the pro-inflammatory response compared to all other devices, with a reduced cell accumulation and fewer foreign body giant cells. The ECM coating degraded by 35 days, and was replaced with loose connective tissue compared to the dense collagenous tissue associated with the uncoated polypropylene mesh device. Biaxial mechanical characterization showed that all of the mesh devices were of similar isotropic stiffness. Upon explanation, the light-weight mesh devices were more compliant than the coated or uncoated heavy-weight devices. This study shows that an ECM coating alters the default host response to a polypropylene mesh, but not the mechanical properties in an acute in vivo abdominal repair model.