Bio-Instructive Scaffolds for Musculoskeletal Tissue Engineering and Regenerative Medicine

Justin Brown, Sangamesh G. Kum bar, Brittany Banik

• Publisher: Academic Press
• Year: 2016
• Print ISBN: 9780128033944
• eBook ISBN: 9780128033999
• Topic: Tecnologia e ingegneria
• Subtopic: Biotecnologia in medicina

Bio-Instructive Scaffolds for Musculoskeletal Tissue Engineering and Regenerative Medicine explores musculoskeletal tissue growth and development across populations, ranging from elite athletes to the elderly. The regeneration and reparation of musculoskeletal tissues present the unique challenges of requiring both the need to withstand distinct forces applied to the body and ability to support cell populations.The book is separated into sections based on tissue type, including bone, cartilage, ligament and tendon, muscle, and musculoskeletal tissue interfaces. Within each tissue type, the chapters are subcategorized into strategies focused on cells, hydrogels, polymers, and other materials (i.e. ceramics and metals) utilized in musculoskeletal tissue engineering applications.In each chapter, the relationships that exist amongst the strategy, stem cell differentiation and somatic cell specialization at the intracellular level are emphasized. Examples include intracellular signaling through growth factor delivery, geometry sensing of the surrounding network, and cell signaling that stems from altered population dynamics.- Presents a self-contained work for the field of musculoskeletal tissue engineering and regenerative medicine- Focuses on how materials of structures can be designed to be resistant while promoting viable grafts- Contains major tissue types that are covered with a strategy for each material and structure

Part I

Introduction

Chapter 1

Bio-Instructive Cues in Scaffolds for Musculoskeletal Tissue Engineering and Regenerative Medicine

K.L. Collins^a; E.M. Gates^a; C.L. Gilchrist; B.D. Hoffman Duke University, Durham, NC, United States
^a These authors contributed equally.

Abstract

In vivo, cells are presented with complex and dynamic stimuli from their surrounding microenvironment. These microenvironmental cues direct an array of cell behaviors that are critical to tissue development and regeneration, including differentiation, growth, and extracellular matrix (ECM) assembly. Tissue engineers have utilized knowledge of the microenvironment to design biomimetic, “instructive” scaffold materials that elicit an array of desired downstream cellular responses. The central challenge in bioinstructive scaffold design involves controlling cell behavior, specifically determining the signals or input instructions that are necessary to direct cells to assemble and maintain a new functional tissue for repair or replacement. Biochemical components within the microenvironment, including growth factors and cytokines, have well-established functions in regulating cell behavior, and some success has been achieved recapitulating these biochemical signals within scaffold microenvironments. However, emerging evidence has demonstrated that biophysical aspects of a cell's microenvironment may have equally important and analogous roles in regulating cell behavior. Two cellular structures, focal adhesions and adherens junctions, are thought to be key mediators in sensing and responding to the biophysical microenvironment, playing critical roles in cell migration, force-sensitive gene regulation, differentiation, and ECM assembly. Significant advancement in the field of tissue engineering requires a greater understanding of both how cells detect and interpret biophysical cues through these structures, as well as the dynamic interactions between biochemical and biophysical stimuli. This improved mechanistic understanding can then be used to guide scaffold design, explicitly targeting these structures to control downstream cell behavior and improve tissue regeneration outcomes.

Keywords

Tissue engineering; Microenvironment; Mechanotransduction; Mechanosensing; Scaffolds

1.1 Introduction

The primary goal of the field of tissue engineering is the generation of biological substitutes to repair tissues damaged by injury, disease, or aging. When tissue engineering emerged in the mid-20th century, initial efforts focused on treatments for skin wounds of burn victims [1]. These treatments involved the cultivation, preservation, and transplantation of skin from various sources, including specimens from the same species, termed allografts, as well as those from different species, termed xenografts [2–4]. Despite some success, both allografts and xenografts had many drawbacks: there was a high degree of variability between donors, tissue preservation was challenging, and disease transmission from donor to patient was possible [5–7]. To overcome these obstacles, researchers began to investigate ways to create artificial tissues by cultivating cells in vitro and placing them on or within biomaterial scaffolds that provided adhesive and mechanical support for neotissue growth, giving rise to the primary components of modern day tissue engineering [8,9]. A major advance in tissue engineering occurred with the discovery that a patient's own stem cells could be harvested, cultivated, and re-implanted for therapeutic effect, with precautions taken to control pluripotency and differentiation [10]. Over the past several decades since these key developments, researchers have investigated an array of new bio-scaffold materials (both synthetic and naturally derived), fabrication techniques, stem cell sources, and differentiation protocols—all with the goal of creating new functional tissues for repair or replacement. At the heart of this field lies the central challenge of controlling cell behavior: determining which signals or input instructions are necessary to direct cells to assemble and maintain a new functional tissue. Towards this end, much effort has focused on engineering the environment immediately surrounding the cells, termed the cellular microenvironment, to affect key cell behaviors, including growth, migration, and differentiation.

1.1.1 Role of the Cellular Microenvironment

In vivo, cells reside within a complex and dynamic microenvironment that provides a variety of biochemical and biophysical cues to the cell. In recent years there has been an increasing recognition of both the complexity of the cellular microenvironment and its importance in directing cell behaviors. This is of particular relevance to the field of tissue engineering, where microenvironmental cues have been shown to direct an array of cell behaviors critical to tissue development and regeneration, including differentiation, growth, migration, and extracellular matrix (ECM) production and assembly [11–13]. The primary components of the cellular microenvironment include soluble biochemicals, the insoluble ECM, and other nearby cells. It has been well established that soluble biochemical molecules such as growth factors, morphogens, and hormones can strongly influence cell behavior and stem cell differentiation [14]; however, only more recently have studies revealed that the native ECM and other adjacent cells, in addition to providing structural and adhesive support, also regulate key aspects of cell function by presenting a variety of biochemical and biophysical cues [15]. Thus, all aspects of the microenvironment should be considered potent regulators of cell behavior. In order to faithfully recapitulate complex tissue structure and function, it is necessary to determine not only which of these microenvironmental signals are critical in directing specific cell behaviors, but also the manner in which they are presented to cells.

1.1.2 Current Challenges

A major emphasis in the field of tissue engineering is the development of biomaterials, most commonly bioinstructive scaffolds, which incorporate a variety of microenvironmental cues to direct cell behaviors. Specifically, studies have examined the effects of specific ECM ligands, scaffold topographies or architecture, and mechanical properties such as stiffness on cell behavior and tissue formation [12,16–19]. While these studies have significantly improved our understanding of the roles of particular cues, they have also demonstrated that presenting a single or a few select cues may not be sufficient to generate a fully functional tissue, with neotissues often falling short of native tissue structure and function. These findings suggest that the successful recapitulation of complex combinations of cues is likely necessary to achieve fully functional tissues. As the cellular microenvironment contains a wealth of biochemical and biophysical cues that are often interconnected, a key challenge in tissue engineering is to understand which of these cues are necessary in directing formation of a specific functional tissue. Therefore, a more complete understanding of how cells sense, interpret, and convert these microenvironmental cues into downstream biochemical responses is needed to accelerate the advancement of tissue engineering approaches. Ideally, this mechanistic understanding will eventually enable the “rational” design of new biomaterials that specifically control these cellular signaling systems to affect tissue-level outcomes.

In this chapter, we will examine the roles of both chemical and physical cell regulators within the cellular microenvironment. We will begin by defining key aspects of the ECM and describing methods for their recapitulation. We will then discuss several key cell signaling pathways important in the detection of the cellular microenvironment, with particular emphasis on those involved in the sensing of biophysical microenvironmental cues. An emerging theme in the field is that an understanding of the specific cell signaling pathways that a given environmental cue regulates will be necessary for the development of rationally designed bioinstructive scaffolds.

1.2 The Cellular Microenvironment: Key Aspects

1.2.1 What is the Microenvironment?

The cellular microenvironment is de...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Part I: Introduction
• Part II: Bone
• Part III: Tendon/Ligament
• Part IV: Cartilage
• Part V: Muscle
• Part VI: Musculoskeletal Interfaces
• Index