Biomaterials in Regenerative Medicine and the Immune System

Myocardial infarction (MI) is a potentially lethal condition and remains one of the leading causes of death. Since heart tissue has a diminished capacity to regenerate itself, the current goal is to replace the damaged tissue with repair cells that have the capacity to recover heart function. Among the methods being investigated include the use of human-derived mesenchymal stem cell (MSC). Although these cells have not been shown to effectively produce functional cardiomyocytes, they have shown great potential to improve angiogenesis and cardiac function. Engineered cardiac patches composed of hMSCs and a biomaterial will inevitably be subjected to the inflammatory environment that follows the MI, and these interactions will play a crucial role during the remodeling process. This chapter describes the inflammatory environment found after an MI followed by a description of how MSCs can be used as part of a cardiac patch that can modulate the inflammatory response to improve healing.

Biomaterials are part of the solution to many unmet clinical needs, from implantable sensors to drug delivery devices and engineered tissues. However, biomaterials face an inflammatory environment upon implantation, representing a potential obstacle to their success. In this chapter, we review the consequences of the foreign body response (FBR) for biomaterial function and strategies that have been used to inhibit the FBR. We focus on the role of the macrophage, the cell at the center of the inflammatory response, and discuss implications of changing macrophage behavior on biomaterial acceptance or rejection. Finally, we discuss recent discoveries in the role of macrophage phenotype, ranging from pro-inflammatory (M1) to anti-inflammatory (M2), and the role it plays in wound healing and biomaterial vascularization. We conclude with a discussion of biomaterial design strategies that have been suggested to positively interact with and potentially control macrophages in order to improve interactions with the inflammatory response.

The role of tissue and immune microenvironments has played a large role in fields such as tumor immunology. Recently, there has been interest in the role of the immune microenvironment in tissue engineering, more specifically how that environment can influence regeneration. Immune cells secrete a diverse repertoire of signaling molecules that can influence other immune cells as well as surrounding parenchyma. In regenerating tissues, these signaling molecules become very important in tissue growth and differentiation. In vitro studies include the role of a scaffold in macrophage polarization, a critical determinant in regenerative success. In vivo innate and adaptive immune responses to varying scaffolds give us insights into the correct scaffold to choose for the goal tissue to be regenerated. By combining the optimum regenerative immune environment with the innate polarization tendencies of scaffolds, we will be better able to cater specific scaffolds to their applications and improve clinical outcomes.

Inertness, mechanical strength, or biocompatibility are those attributes that allow many polymeric materials to be successfully integrated into biological systems or utilized in biomedical devices, but not without adverse effects. One of the ongoing problems is the formation of microbial films that are often detrimental and deadly. This chapter discusses potential surface modifications of polymeric materials utilized in biomedical applications that inhibit bacterial growth. While recent studies reveal a number of short-term approaches, covalent attachment of multilayers (CAM) to tether pH-responsive “switching” polyelectrolytes is a long-term alternative. Synthetic paths to covalently attach bacteriophages (phages) to synthetic polymeric surfaces while maintaining bacteriophage’s biological activities capable of killing deadly human pathogens are also explored. This alternative approach of fighting microbial wars on polymeric surfaces may be considered as a long-term alternative to inhibit early stages of microbial film formation.

We discuss the use of layer-by-layer (LbL) films as a powerful platform for engineering multifunctional antibacterial coatings for biomedical devices. These coatings can be designed to incorporate a variety of bioactive antimicrobial molecules, including antibiotics, cationic peptides, biofilm-disrupting and Q-sensing agents, and immunoregulatory cytokines. Here, we focus on active rather than passive delivery of antimicrobials from the coatings achieved through temperature or pH variations, as well as through the application of electric field. Of particular interest are “self-defensive” coatings which are activated in the presence of pathogens by pathogen-specific molecules or by acidification of the immediate environment by pathogenic bacteria. We describe several types of these coatings, which can carry high payloads of antimicrobials but do not release them at normal physiological conditions at pH 7.5 until the arrival of a bacterial trigger. Importantly, these coatings inhibit bacterial colonization while simultaneously promoting a healthy tissue response.

Naturally occurring antimicrobial peptides (AMPs) have been proposed as blueprints for the development of new antimicrobials to combat the widespread emergence of bacterial resistance. Though early work in the field has predominantly focused on their broad-spectrum antimicrobial activity, mounting evidence suggests that the immunomodulating properties of these innate defense molecules may be as critical for their development into potent therapeutic agents. In this chapter, the biological activities of both natural and synthetic multifunctional host defense peptides (HDPs) are discussed, with a focus on design strategies aimed at bestowing these molecules with superior antimicrobial and immune-regulating properties, their potential clinical applications, and challenges hampering the transition of these therapeutic agents from the benchtop to the clinic.

Blood is responsible for providing tissues with nutrients via plasma and also transporting cellular components for gas exchange, immune surveillance, and hemostatic responses. Blood transfusion is a clinical mainstay in the management of bleeding complications and congenital blood disorders. Therefore, there is a high clinical emphasis on blood donation and refinement of the collection, storage, and transport strategies of natural blood products. However, these products are often short in supply, require meticulous antigen matching, and pose risks of pathological contamination and biologic side effects. Consequently, there is significant clinical interest in synthetic blood substitutes. To this end, biomaterials provide unique ways of designing blood cell mimics and plasma substitutes. In parallel to synthetic blood substitutes, currently research is also being focused on generating blood cells from stem cells. This chapter provides a comprehensive discussion of the various blood product designs highlighting the biomaterials-based applications and approaches in this field.

Modulation of the immune system through the use of biomaterials provides opportunities for new applications in the field of regenerative medicine to be translated into clinical settings. Particularly, biomaterials-based immunomodulation targeting dendritic cells has gained much interest in recent years. Dendritic cells are professional antigen-presenting cells serving as the bridge between innate and adaptive immunity, and they capture, process, and present antigen to naïve T cells to further dictate immune response outcomes. Current biomaterials-based technologies targeting dendritic cells have focused on inducing either inflammatory or suppressive phenotypes through the use of particulates or scaffolds, the modulation of material properties, and the delivery of proteins, nucleic acids, and small drug molecules. This chapter provides relevant immunology concepts, an overview of dendritic cells and their functions, and highlights exciting new biomaterials-based techniques employed for use in cancer, infectious and autoimmune diseases, and transplant rejection.

Advances in engineered nanoformulations for immunotherapeutic drug delivery have accompanied the rapidly growing interest in clinical immunotherapy. Several material systems have been developed that confer improved efficacy by overcoming delivery barriers detrimental to drug bioactivity. Notable examples include strategies that prolong drug circulation times and enhance the delivery of immunotherapeutic drugs to lymphoid tissues enriched in immune cells important in the initiation and regulation of immune response. The utility of material nanoformulations to facilitate co-delivery of multiple drugs with synergistic activity has also been demonstrated, as has the potential for drug delivery and immunotherapeutic activity to be enhanced via receptor-mediated targeting. Important innovations have furthermore led to the development of triggered drug release mechanisms that increase the control of drug bioactivity within targeted subcellular compartments and/or tissues. This chapter details how materials engineering, formulation design, and delivery schemes have improved immunological outcomes in a variety of therapeutic applications.

Recent progress in our understanding of tumor biology, cell–matrix interactions, and immune response has facilitated the development of innovative biomaterials, therapeutic delivery, and tissue-engineering approaches to modulate cancer. In this chapter, we provide a summary of the recent developments and highlight the unique material-based approaches for tumor vascularization, targeted therapy, organoids for tumor microenvironment, and immunotherapy. We briefly discuss the immune microenvironment and checkpoints and how they play a role in tumor-mediated immune suppression. Finally, we provide an overview of challenges and future direction in biomaterials-based modulation of cancer.

Dendritic cells (DCs) are attractive targets for therapies aimed at enhancing or diminishing immunity. The delivery of antigens to DCs can effectively modify antigen-specific T cell responses and provides a strategy for enhancing vaccines which require potent T cell responses. Furthermore, in the absence of adjuvant delivery of antigen to DCs induces antigen-specific T cell anergy, providing a potential method for treating autoimmune diseases. Encapsulation of cargoes including antigens and adjuvants into nanoparticles (NPs) provides a promising method for in situ delivery to DCs. However, DCs are heterogeneous and their subsets mediate disparate functions. Therefore, to achieve effective T cell responses, the design of any NP platform must take into account which DC subset(s) needs to be targeted. In this chapter, we discuss how the function of DC subsets differ, how this impacts NP design, and outline recent promising novel NP platforms that may be suitable for DC targeting.

Biomaterials, ranging from basic cellulose-based systems to advanced superabsorbent peptidic hydrogels, form an inherent component of wound dressings currently under research and in clinical practice. Given the inflamed, open, and moist nature of wounds, the damaged dermal layers are exposed both to internal (inflammatory cytokines) and external (infection) factors requiring immediate localized intervention which can provide therapeutic action and environmental protection. Although several biomaterials conform to one or more prerequisites of a wound dressing such as hydration balance, biomimicry with the underlying tissue, cell adhesion, antiinfective properties, water vapor and gas transmission, bioresorbability and controlled biodegradation, porous architecture, and easy clinical and processing handling, a “single” biomaterial fulfilling “all-of-the-above” characteristics is yet to be discovered. This chapter provides a concise description of recent developments in integrated biomaterial archetypes—such as multipolymeric systems, composite nanofibrous structures, and inorganically modified polymer networks—encompassing “most-of-the-above” wound dressing desirabilities.

Total joint replacement (TJR) is a highly successful surgical intervention that relieves pain and improves function. Medical-grade polymers are commonly used in TJRs. Fortunately, most TJRs last for decades. However, excessive use of the TJR and impact-loading activities are generally prohibited due to potential fracture and degradation of the cement mantle and excessive wear of the polyethylene-articulating surface. Polymer wear particles and by-products stimulate the innate immune system. This manifests as a chronic inflammatory and foreign body reaction that may result in periprosthetic osteolysis, undermining the connection of the implant to bone. This leads to loss of fixation and painful loosening of the implant. This chapter outlines fundamental, clinical, material, and biological information in relation to the use of polymers in TJRs and the adverse effects associated with polymer wear debris.

Antigen-specific immune modulation and bioengineered immunotherapy have many applications in medicine. One promising technology to achieve the goal of immune control is the use of artificial antigen-presenting cells (aAPCs). aAPCs are synthetic constructs that mimic natural APCs in their ability to direct and maintain a T cell response. Several design criteria are important in the construction of an aAPC including its biomaterial composition, the size and shape of the aAPC for T cell interaction, the type and density of surface proteins presented, the delivery of soluble signals, and the recreation of the dynamic immunological synapse. Various aAPCs have been developed as therapeutics including those that activate the immune system against cancer or infectious disease and others that suppress the immune system in the context of autoimmunity. Additional research into the design and application of aAPCs could unlock the full potential of this technology to direct the immune response.