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Upon implantation into a patient, any biomaterial induces a cascade of immune responses that influences the outcome of that device. This cascade depends upon several factors, including the composition of the material itself and the location in which the material is implanted. There is still significant uncertainty around the role of different tissue microenvironments in the immune response to biomaterials and how that may alter downstream scaffold remodeling and integration. In this study, we present a study evaluating the immune response to decellularized extracellular matrix materials within the intraperitoneal cavity, the subcutaneous space, and in a traumatic skeletal muscle injury microenvironment. All different locations induced robust cellular recruitment, specifically of macrophages and eosinophils. The latter was most prominent in the subcutaneous space. Intraperitoneal implants uniquely recruited B cells that may alter downstream reactivity as adaptive immunity has been strongly implicated in the outcome of scaffold remodeling. These data suggest that the location of tissue implants should be taken together with the composition of the material itself when designing devices for downline therapeutics. Different tissue locations have unique immune microenvironments, which can influence the immune response to biomaterial implants. By considering the specific immune profiles of the target tissue, researchers can develop implant materials that promote better integration, reduce complications, and improve the overall outcome of the implantation process. [Display omitted] [ABSTRACT FROM AUTHOR]

Due to the limited capacity of mammals to regenerate complex tissues, researchers have worked to understand the mechanisms of tissue regeneration in organisms that maintain that capacity. One example is the MRL/MpJ mouse strain with unique regenerative capacity in ear pinnae that is absent from other strains, such as the common C57BL/6 strain. The MRL/MpJ mouse has also been associated with an autoimmune phenotype even in the absence of the mutant Fas gene described in its parent strain MRL/lpr. Due to these findings, the differences between the responses of MRL/MpJ versus C57BL/6 strain are evaluated in volumetric muscle injury and subsequent material implantation. One salient feature of the MRL/MpJ response to injury is robust adipogenesis within the muscle. This is associated with a decrease in M2‐like polarization in response to biologically derived extracellular matrix scaffolds. In pro‐fibrotic materials, such as polyethylene, there are fewer foreign body giant cells in the MRL/MpJ mice. As there are reports of both positive and negative influences of adipose tissue and adipogenesis on wound healing, this model can provide an important lens to investigate the interplay between stem cells, adipose tissue, and immune responses in trauma and material implantation. [ABSTRACT FROM AUTHOR]

Tissue clearing of whole intact organs has enhanced imaging by enabling the exploration of tissue structure at a subcellular level in three‐dimensional space. Although clearing and imaging of the whole organ have been used to study tissue biology, the microenvironment in which cells evolve to adapt to biomaterial implants or allografts in the body is poorly understood. Obtaining high‐resolution information from complex cell–biomaterial interactions with volumetric landscapes represents a key challenge in the fields of biomaterials and regenerative medicine. To provide a new approach to examine how tissue responds to biomaterial implants, we apply cleared tissue light‐sheet microscopy and three‐dimensional reconstruction to utilize the wealth of autofluorescence information for visualizing and contrasting anatomical structures. This study demonstrates the adaptability of the clearing and imaging technique to provide sub‐cellular resolution (0.6 μm isotropic) 3D maps of various tissue types, using samples from fully intact peritoneal organs to volumetric muscle loss injury specimens. Specifically, in the volumetric muscle loss injury model, we provide 3D visualization of the implanted extracellular matrix biomaterial in the wound bed of the quadricep muscle groups and further apply computational‐driven image classification to analyze the autofluorescence spectrum at multiple emission wavelengths to categorize tissue types at the injured site interacting with the biomaterial scaffolds. [ABSTRACT FROM AUTHOR]

Research on the foreign body response (FBR) to biomaterial implants has been focused on the roles that the innate immune system has on mediating tolerance or rejection of implants. However, the immune system also involves the adaptive immune response and it must be included in order to form a complete picture of the response to biomaterials and medical implants. In this review, we explore recent understanding about the roles of adaptive immune cells, specifically T cells, in modulating the immune response to biomaterial implants. The immune response to implants elicits a delicate balance between tissue repair and fibrosis that is mainly regulated by three types of T helper cell responses –T helper type 1, T helper type 2, and T helper type 17– and their crosstalk with innate immune cells. Interestingly, many T cell response mechanisms to implants overlap with the process of fibrosis or repair in different tissues. This review explores the fibrotic and regenerative T cell biology and draws parallels to T cell responses to biomaterials. Additionally, we also explore the biomedical engineering advancements in biomaterial applications in designing particle and scaffold systems to modulate T cell activity for therapeutics and devices. Not only do the deliberate engineering design of physical and chemical material properties and the direct genetic modulation of T cells not only offer insights to T cell biology, but they also present different platforms to develop immunomodulatory biomaterials. Thus, an in-depth understanding of T cells' roles can help to navigate the biomaterial-immune interactions and reconsider the long-lasting adaptive immune response to implants, which, in the end, contribute to the design of immunomodulatory medical implants that can advance the next generation of regenerative therapy. This review article integrates knowledge of adaptive immune responses in tissue damage, wound healing, and medical device implantation. These three fields, often not discussed in conjunction, are important to consider when evaluating and designing biomaterials. Through incorporation of basic biological research alongside engineering research, we provide an important lens through which to evaluate adaptive immune contributions to regenerative medicine and medical device development. [Display omitted] [ABSTRACT FROM AUTHOR]

Urinary bladder matrix (UBM) is used clinically for management of wounds and reinforcement of surgical soft tissue repair, among other applications. UBM consists of the lamina propria and basal lamina of the porcine urinary bladder, and is decellularized as part of the process to manufacture the medical device. UBM is composed mainly of Collagen I, but also contains a wide variety of fibrillar and basement membrane collagens, glycoproteins, proteoglycans and ECM-associated factors. Upon application of the biomaterial in a traumatic or non-traumatic setting in a mouse model, there is a cascade of immune cells that respond to the damaged tissue and biomaterial. Here, through the use of multicolor flow cytometry, we describe the various cells that infiltrate the UBM scaffold in a subcutaneous and volumetric muscle injury model. A wide variety of immune cells are found in the UBM scaffold immune microenvironment (SIM) including F4/80 + macrophages, CD11c + dendritic cells, CD3 + T cells and CD19 + B cells. A systemic IL-4 upregulation and a local M2-macrophage response were observed in the proximity of the implanted UBM. The recruitment and activation of these cells is dependent upon signals from the scaffold and communication between the different cell types present. [ABSTRACT FROM AUTHOR]

Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/ Rictor-dependent T helper 2 pathway that guides interleukin-4-dependent macrophage polarization, which is critical for functionalmuscle recovery. Manipulating the adaptive immune systemusing biomaterials engineeringmay support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair. [ABSTRACT FROM AUTHOR]