The host innate immune response to a surgical mesh is arguably the most important determinant of tissue remodeling and functional outcome. Macrophage phenotype and the associated secretion of pro-inflammatory or anti-inflammatory cytokines during the first 10–14 days following implantation has been strongly associated with downstream events such as chronic inflammation vs. functional tissue remodeling, respectively, and the associated clinical consequences. A persistent, pro-inflammatory (M1-like) macrophage phenotype is typically associated with fibrosis and scarring. In contrast, an early transition to a regulatory, pro-remodeling (M2-like) macrophage phenotype is predictive of organized, site-appropriate connective tissue deposition. The ratio of M2-like to M1-like macrophages in the early post-implantation period defines the microenvironmental milieu and the associated tissue response. The present study evaluated the early macrophage response to a synthetic non-resorbable (Bard® Mesh), synthetic resorbable (TIGR® Matrix Surgical Mesh and GORE® BIO-A® Tissue Reinforcement), synthetic mesh composed of the naturally occurring molecule 4-hydroxybutyrate, (Phasix™ Mesh), and a biologic surgical mesh composed of dermal extracellular matrix (Strattice™ Reconstructive Tissue Matrix); all of which are used in ventral hernia repair. The spatiotemporal distribution of pro-inflammatory (CD68+CD86+TNF-α+) and pro-remodeling (CD68+CD206+) macrophages, and the remodeling response in terms of vascularization, total number of infiltrating cells, presence of multinucleate giant cells (MNGC), and cell layer thickness around the implanted materials was evaluated at 3, 7, 14, 21, and 35 days post implantation. Results showed an association of the synthetic non-resorbable and resorbable meshes with a robust, pro-inflammatory response within 3 days of implantation, and an increased presence of MNGC around the mesh fibers at longer time points. Phasix™ Mesh was associated with an increased presence of M2-like macrophages immediately adjacent to the mesh fibers at earlier time points, and a favorable tissue remodeling outcome at 35 days. Results of the present study are consistent with the premise that an early shift of M1-like to M2-like macrophages is associated with favorable outcomes, including reduced fibrosis, at later time points.

Naturally occurring antimicrobial peptides (AMPs) are effector molecules secreted by several cell types but especially by cells of the innate immune system such as macrophages. AMPs largely avoid resistance acquired by bacteria to man-made antibiotics. Different short chain fatty acids (SCFAs) have proven to be efficient inducers of AMP secretion. The SCFA butyrate is an endogenous histone deacetylase inhibitor that has been shown to induce the expression of the AMP cramp (cathelicidin LL-37) in cells of the immune system and mucosal epithelium, which provides protection against pathogens. Clinical applications of butyrate, however, are limited due to its cytotoxic effects. Hydroxylated derivatives of butyrate (2-hydroxybutyrate [2HB], 3-hydroxybutyrate [3HB], and 4-hydroxybutyrate [4HB]) are also endogenous molecules, but their capability of inducing AMP expression has been unexplored. 4HB has been used for the production of polymeric surgical meshes intended for soft tissue repair. This study evaluated the ability of hydroxylated derivatives of butyrate to induce the upregulation of AMPs in murine bone marrow-derived macrophages in vitro. Noncytotoxic effects and increased cramp and -defensin-4 were found to be induced by 4HB. An in vivo increased resistance to deliberate bacterial contamination was shown by a surgical mesh composed of a polymer of 4HB compared with polypropylene surgical mesh. Impact Statement This study evaluated the biological activity of hydroxylated derivatives of butyrate as inductors of antimicrobial peptides (AMPs) in murine bone marrow-derived macrophages in vitro. A differential modulation of AMP expression by the hydroxylated derivatives of butyrate is shown. The ability of sodium 4-hydroxybutyrate to upregulate AMP expression through a histone deacetylase inhibitory-independent mechanism, and to promote increased resistance to bacterial contamination in vivo are also shown. The findings provide an alternative for prevention of bacterial contamination of implanted biomaterials. Functionalization of biomaterials with hydroxylated derivatives of butyrate can enhance the endogenous antimicrobial activity of the immune system through increased production of AMPs by host cells, thus providing protection against bacterial contamination.

Mounting evidence suggests that site-appropriate loading of implanted extracellular matrix (ECM) bioscaffolds and the surrounding microenvironment is an important tissue remodeling determinant, although the role at the cellular level in ECM-mediated skeletal muscle remodeling remains unknown. This study evaluates crosstalk between progenitor cells and macrophages during mechanical loading in ECM-mediated skeletal muscle repair. Myoblasts were exposed to solubilized ECM bioscaffolds and were mechanically loaded at 10% strain, 1 Hz for 5 h. Conditioned media was collected and applied to bone marrow-derived macrophages followed by immunolabeling for proinflammatory M1-like markers and proremodeling M2-like markers. Macrophages were subjected to the same loading protocol and their secreted products were collected for myoblast migration, proliferation, and differentiation analysis. A mouse hind limb unloading volumetric muscle loss model was used to evaluate the effect of loading upon the skeletal muscle microenvironment after ECM implantation. Animals were sacrificed at 14 or 180 days. Isometric torque production was tested and tissue sections were immunolabeled for macrophage phenotype and muscle fiber content. Results show that loading augments the ability of myoblasts to promote an M2-like macrophage phenotype following exposure to ECM bioscaffolds. Mechanically loaded macrophages promote myoblast chemotaxis and differentiation. Lack of weight bearing impaired muscle remodeling as indicated by Masson's Trichrome stain. Isometric torque was significantly increased following ECM implantation when compared to controls, a response not present in the hind limb-unloaded group. This work provides an important mechanistic insight of the effects of rehabilitation upon ECM-mediated remodeling and could have broader implications in clinical practice, advocating multidisciplinary approaches to regenerative medicine, emphasizing rehabilitation.

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 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.

Volumetric muscle loss (VML) is a severe and debilitating clinical problem. Current standard of care includes physical therapy or orthotics, which do not correct underlying strength deficits, and surgical tendon transfers or muscle transfers, which involve donor site morbidity and fall short of restoring function. The results of a 13-patient cohort study are described herein and involve a regenerative medicine approach for VML treatment. Acellular bioscaffolds composed of mammalian extracellular matrix (ECM) were implanted and combined with aggressive and early physical therapy following treatment. Immunolabeling of ultrasound-guided biopsies, and magnetic resonance imaging and computed tomography imaging were performed to analyse the presence of stem/progenitor cells and formation of new skeletal muscle. Force production, range-of-motion and functional task performance were analysed by physical therapists. Electrodiagnostic evaluation was used to analyse presence of innervated skeletal muscle. This study is registered with ClinicalTrials.gov, numbers NCT01292876. In vivo remodelling of ECM bioscaffolds was associated with mobilisation of perivascular stem cells; formation of new, vascularised, innervated islands of skeletal muscle within the implantation site; increased force production; and improved functional task performance when compared with pre-operative performance. Compared with pre-operative performance, by 6 months after ECM implantation, patients showed an average improvement of 37.3% ( P <0.05) in strength and 27.1% improvement in range-of-motion tasks ( P <0.05). Implantation of acellular bioscaffolds derived from ECM can improve strength and function, and promotes site-appropriate remodelling of VML defects. These findings provide early evidence of bioscaffolding as a viable treatment of VML.

Acellular biologic scaffolds derived from extracellular matrix have been investigated in preclinical and clinical studies as a regenerative medicine approach for volumetric muscle loss treatment. The present manuscript provides a review of previous studies supporting the use of extracellular matrix derived biologic scaffolds for the promotion of functional skeletal muscle tissue formation that is contractile and innervated. The manuscript also identifies key mechanisms that have been associated with ECM-mediated skeletal muscle repair, and provides hypotheses as to why there have been variable outcomes, ranging from successful to unsatisfactory, associated with ECM bioscaffold implantation in the skeletal muscle injury microenvironment

Event Abstract Back to Event Degradation products of extracellular matrix bioscaffolds derived from diverse source tissues differentially influence macrophage phenotype Jenna L. Dziki1, 2, Derek S. Wang1, Catalina Pineda1, 2, Brian M. Sicari1, 3 and Stephen F. Badylak1, 2, 3 1 University of Pittsburgh, McGowan Institute for Regenerative Medicine, United States 2 University of Pittsburgh, Department of Bioengineering, United States 3 University of Pittsburgh, Department of Surgery, United States Extracellular matrix (ECM) bioscaffolds are widely used to facilitate constructive tissue remodeling[1]-[4], a process that relies upon the infiltration and polarization of host macrophages toward an immunomodulatory, M2 phenotype. While a clear temporal association exists between an M2 macrophage response and downstream remodeling[5]-[8], the ability of ECM bioscaffolds to directly affect macrophage phenotype has not been clearly established. The objective of the present study was to investigate the influence of ECM bioscaffolds on macrophage phenotype. Phenotype was established by surface markers, gene expression, participation in progenitor cell cross talk, and phagocytic capacity. Primary bone marrow derived macrophages from C57bl/6 mice were exposed to 200 ug/ml of pepsin-digested ECM. Control M1 and M2 polarized macrophages were derived by exposure to IFN-y/LPS and IL-4, respectively. Cells were fixed and immunolabeled for indicators of M1 (iNOS) vs M2 (Fizz1) macrophages. Western blotting, flow cytometry, and qPCR were performed to corroborate immunolabeling results. Macrophage secreted products were used to determine chemotaxis, proliferation, and differentiation of progenitor cells via a Boyden chamber, BrdU incorporation, and differentiation marker expression, respectively. Secreted products from macrophages or ECM bioscaffold degradation products produced by pepsin-digestion were used to examine antimicrobial activity. Phagocytosis was examined using fluorophore-conjugated bioparticles. Macrophage metabolism was analyzed using an MTT assay. The present study shows that degradation products of ECM derived from a variety of tissues (e.g. small intestinal submucosa, urinary bladder, esophagus, brain, and spinal cord) promote a Fizz1+, M2-like macrophage phenotype. Preliminary results suggest ECM-treated macrophages acquire a phenotype unique from the IL-4 induced, M2 phenotype with respect to gene expression and phagocytic function. Together, these results indicate ECM degradation products directly promote constructive macrophage phenotypes, which recruit and promote differentiation of progenitor cells, suggesting a possible mechanism for ECM-mediated remodeling. References:[1] Wainwright JM, et al. (2010) Preparation of cardiac extracellular matrix from an intact porcine heart. Tissue engineering. Part C, Methods 16(3):525-532.[2] Sicari BM, et al. (2012) A murine model of volumetric muscle loss and a regenerative medicine approach for tissue replacement. Tissue engineering. Part A 18(19-20):1941-1948.[3] Badylak SF, et al. (2011) 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 17(11-12):1643-1650.[4] Turner NJ & Badylak SF (2013) Biologic scaffolds for musculotendinous tissue repair. European cells & materials 25:130-143.[5] Brown BN, Valentin JE, Stewart-Akers AM, McCabe GP, & Badylak SF (2009) Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. Biomaterials 30(8):1482-1491.[6] Brown BN, Valentin JE, Stewart-Akers AM, McCabe GP, & Badylak SF (2009) Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. Biomaterials 30(8):1482-1491.[7] Badylak SF, Valentin JE, Ravindra AK, McCabe GP, & Stewart-Akers AM (2008) Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue engineering. Part A 14(11):1835-1842.[8] Brown BN, et al. (2012) Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials. Acta biomaterialia 8(3):978-987.[9] Brown BN, Ratner BD, Goodman SB, Amar S, & Badylak SF (2012) Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials 33(15):3792-3802. Keywords: Extracellular Matrix, biomaterial, acellullar matrix, matrix-cell interaction Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: Poster Topic: Biomaterials in immune response Citation: Dziki JL, Wang DS, Pineda C, Sicari BM and Badylak SF (2016). Degradation products of extracellular matrix bioscaffolds derived from diverse source tissues differentially influence macrophage phenotype. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.01987 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jenna L Dziki Derek S Wang Catalina Pineda Brian M Sicari Stephen F Badylak Google Jenna L Dziki Derek S Wang Catalina Pineda Brian M Sicari Stephen F Badylak Google Scholar Jenna L Dziki Derek S Wang Catalina Pineda Brian M Sicari Stephen F Badylak PubMed Jenna L Dziki Derek S Wang Catalina Pineda Brian M Sicari Stephen F Badylak Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Acellular bioscaffolds composed of extracellular matrix (ECM) have been effectively used to promote functional tissue remodeling in both preclinical and clinical studies of volumetric muscle loss, but the mechanisms that contribute to such outcomes are not fully understood. Thirty-two C57bl/6 mice were divided into eight groups of four animals each. A critical-sized defect was created in the quadriceps muscle and was repaired with a small intestinal submucosa ECM bioscaffold or left untreated. Animals were sacrificed at 3, 7, 14, or 56 days after surgery. The spatiotemporal cellular response in both treated and untreated groups was characterized by immunolabeling methods. Early time points showed a robust M2-like macrophage phenotype following ECM treatment in contrast to the predominant M1-like macrophage phenotype present in the untreated group. ECM implantation promoted perivascular stem cell mobilization, increased presence of neurogenic progenitor cells, and was associated with myotube formation. These cell types were present not only at the periphery of the defect near uninjured muscle, but also in the center of the ECM-filled defect. ECM bioscaffolds modify the default response to skeletal muscle injury, and provide a microenvironment conducive to a constructive healing response.

The most commonly used tissue engineering approach includes the ex vivo combination of site-appropriate cell(s) and scaffold material(s) to create three-dimensional constructs for tissue replacement or reconstruction. These three-dimensional combinations are typically subjected to a period of culture and conditioning (i.e., self-assembly and maturation) to promote the development of ex vivo constructs which closely mimic native target tissue. This cell-based approach is challenged by the host response to the engineered tissue construct following surgical implantation. As an alternative to the cell-based approach, acellular biologic scaffolds attract endogenous cells and remodel into partially functional mimics of native tissue upon implantation. The present review examines cell-types (i.e., seed), scaffold materials (i.e., soil), and challenges associated with functional tissue engineering. Skeletal muscle is used as the target tissue prototype but the discussed principles will largely apply to most body systems.

Background Electrodiagnosis can reveal the nerve and muscle changes following surgical placement of an extracellular matrix (ECM) bioscaffold for treatment of volumetric muscle loss (VML). Objective The purpose of this study was to characterize nerve conduction study (NCS) and electromyography (EMG) changes following ECM bioscaffold placement in individuals with VML. The ability of presurgical NCS and EMG to be used as a tool to help identify candidates who are likely to display improvements postsurgically also was explored. Design A longitudinal case series design was used. Methods The study was conducted at the McGowan Institute for Regenerative Medicine at the University of Pittsburgh. Eight individuals with a history of chronic VML participated. The intervention was surgical placement of an ECM bioscaffold at the site of VML. The strength of the affected region was measured using a handheld dynamometer, and electrophysiologic evaluation was conducted on the affected limb with standard method of NCS and EMG. All measurements were obtained the day before surgery and repeated 6 months after surgery. Results Seven of the 8 participants had a preoperative electrodiagnosis of incomplete mononeuropathy within the site of VML. After ECM treatment, 5 of the 8 participants showed improvements in NCS amplitude or needle EMG parameters. The presence of electrical activity within the scaffold remodeling site was concomitant with clinical improvement in muscle strength. Limitations This study had a small sample size, and participants served as their own controls. The electromyographers and physical therapists performing the evaluation were not blinded. Conclusions Electrodiagnostic data provide objective evidence of physiological improvements in muscle function following ECM placement at sites of VML. Future studies are warranted to further investigate the potential of needle EMG as a predictor of successful outcomes following ECM treatment for VML.

Tissue engineering and regenerative medicine-based strategies for the reconstruction of functional skeletal muscle tissue have included cellular and acellular approaches. The use of acellular biologic scaffold material as a treatment for volumetric muscle loss (VML) in five patients has recently been reported with a generally favorable outcome. Further studies are necessary for a better understanding of the mechanism(s) behind acellular bioscaffold-mediated skeletal muscle repair, and for combination cell-based/bioscaffold based approaches. The present overview highlights the current thinking on bioscaffold-based remodeling including the associated mechanisms and the future of scaffold-based skeletal muscle reconstruction.

Regenerative medicine, a multi-disciplinary approach that seeks to restore form and function to damaged or diseased tissues and organs, has evolved significantly during the past decade. By adapting and integrating fundamental knowledge from cell biology, polymer science, and engineering, coupled with an increasing understanding of the mechanisms which underlie the pathogenesis of specific diseases, regenerative medicine has the potential for innovative and transformative therapies for heretofore unmet medical needs. However, the translation of novel technologies from the benchtop to animal models and clinical settings is non-trivial and requires an understanding of the mechanisms by which the host will respond to these novel therapeutic approaches. The role of the innate immune system, especially the role of macrophages, in the host response to regenerative medicine based strategies has recently received considerable attention. Macrophage phenotype and function have been suggested as critical and determinant factors in downstream outcomes. The constructive and regulatory, and in fact essential, role of macrophages in positive outcomes represents a significant departure from the classical paradigms of host biomaterial interactions, which typically consider activation of the host immune system as a detrimental event. It appears desirable that emerging regenerative medicine approaches should not only accommodate but also promote the involvement of the immune system to facilitate positive outcomes. Herein, we describe the current understanding of macrophage phenotype as it pertains to regenerative medicine and suggest that improvement of our understanding of context-dependent macrophage polarization will lead to concurrent improvement in outcomes.

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.

The regenerative healing response of injured skeletal muscle is dependent upon a heterogeneous population of responding macrophages, which show a phenotypic transition from the pro-inflammatory M1 to the alternatively activated and constructive M2 phenotype. Biologic scaffolds derived from mammalian extracellular matrix (ECM) have been used for the repair and reconstruction of a variety of tissues, including skeletal muscle, and have been associated with an M2 phenotype and a constructive and functional tissue response. The mechanism(s) behind in-vivo macrophage phenotype transition in skeletal muscle and the enhanced M2:M1 ratio associated with ECM bioscaffold use in-vivo are only partially understood. The present study shows that degradation products from ECM bioscaffolds promote alternatively activated and constructive M2 macrophage polarization in-vitro, which in turn facilitates migration and myogenesis of skeletal muscle progenitor cells.

This chapter discusses mammalian extracellular matrix (ECM) as a biologic scaffold material for tissue engineering applications. ECM has been used as a surgically implantable bioscaffold for the reconstruction of injured or missing tissues. Biologic scaffolds composed of ECM alter the default mammalian injury response and promote constructive and functional tissue remodeling. This chapter reviews ECM bioscaffold preparation and mechanisms of action. Commercially available ECM bioscaffolds and recent clinical applications are also discussed.

The endogenous chemotaxis of cells toward sites of tissue injury and/or biomaterial implantation is an important component of the host response. Implanted biomaterials capable of recruiting host stem/progenitor cells to a site of interest may obviate challenges associated with cell transplantation. An assay for the identification and quantification of chemotaxis induced by surgically placed biologic scaffolds composed of extracellular matrix is described herein.

The well-recognized ability of skeletal muscle for functional and structural regeneration following injury is severely compromised in degenerative diseases and in volumetric muscle loss. Tissue engineering and regenerative medicine strategies to support muscle reconstruction have typically been cell-centric with approaches that involve the exogenous delivery of cells with myogenic potential. These strategies have been limited by poor cell viability and engraftment into host tissue. Alternative approaches have involved the use of biomaterial scaffolds as substrates or delivery vehicles for exogenous myogenic progenitor cells. Acellular biomaterial scaffolds composed of mammalian extracellular matrix (ECM) have also been used as an inductive niche to promote the recruitment and differentiation of endogenous myogenic progenitor cells. An acellular approach, which activates or utilizes endogenous cell sources, obviates the need for exogenous cell administration and provides an advantage for clinical translation. The present review examines the state of tissue engineering and regenerative medicine therapies directed at augmenting the skeletal muscle response to injury and presents the pros and cons of each with respect to clinical translation.