In Situ Tissue Regeneration: Host Cell Recruitment and Biomaterial Design

In Situ Tissue Regeneration

Host Cell Recruitment and Biomaterial Design

Editors

Sang Jin Lee

James J. Yoo

Anthony Atala

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Table of Contents

Cover image

Title page

Dedication

Copyright

List of Contributors

Preface

Part 1. Introduction

Chapter 1. Fundamentals of In Situ Tissue Regeneration

Introduction

Strategy: In Situ Tissue Regeneration

Design Considerations: Biomaterial Scaffolds

Applications of In Situ Tissue Regeneration

Conclusion and Future Directions

List of Acronyms and Abbreviations

Part 2. Endogenous Cell Sources

Chapter 2. Stem Cell Homing

Introduction

Homing of Hematopoietic Stem Cells to Bone Marrow Niches

Changes in the Bone Marrow Level of Chemoattractants for Hematopoietic Stem Cells

Homing of Nonhematopoietic Stem Cells to Damaged Organs

To Modulate Homing Gradients as a Strategy to Deliver Therapeutic Stem Cells to the Damaged Organs

Conclusions

Chapter 3. Immunology: Host Responses to Biomaterials

Introduction

Innate Immunity

Adaptive Immunity

Biomaterials

Conclusion

List of Acronyms and Abbreviations

Chapter 4. Foreign Body Reaction and Stem Cell Responses

Introduction

Implant-Mediated Inflammatory Responses and Stem Cell Recruitment

Fibrocytes—Progenitor Fibrotic Cells—and Their Role in Tissue Reactions to Materials

New Strategies to Engineer Stem Cell Responses for Tissue Regenerations

Conclusions

List of Acronyms and Abbreviations

Part 3. Biochemical and Physical Cues

Chapter 5. Roles of Endogenous Growth Factors and Small Peptides in In Situ Tissue Regeneration

Introduction

Stem Cell Mobilization and Vasculogenesis

Stromal Cell-Derived Factor 1 Alpha

Vascular Endothelial Growth Factor

Granulocyte-Colony Stimulating Factor

Substance-P

Experimental Strategies to Identify Stem Cell Trafficking and Homing Using Candidate Molecules

Conclusion

List of Acronyms and Abbreviations

Chapter 6. Small Molecules: Controlling Cell Fate and Function

Introduction

Target Cells for Small Molecule Regulation in Regenerative Medicine

In Vitro/Ex Vivo Regulation of Human Cells by Small Molecules

Using Small Molecules to Enhance In Vivo Tissue Regeneration

Current Status and Future Directions

Chapter 7. Small RNA Delivery for In Situ Tissue Regeneration

Introduction

Strategies for Small RNAs in Tissue Regeneration

Design Consideration for Small RNA Delivery

Small RNAs for In Situ Tissue Regeneration

Summary and Future Directions

List of Acronyms and Abbreviations

Chapter 8. Micro- and Nanotopographical Cues Guiding Biomaterial Host Response

Introduction

Extracellular Matrix Topography and Its Effect on Cellular Response

Controlled Substrate Topography Guiding In Vivo Host Response

Different Fabrication Techniques Used to Create Micro-/Nanosurface Topography

In Vitro Assessment of Micro- and Nanotopographic Features

Modulation of Surface Topography and Its Effect on Associated In Vivo Response

Summary

Chapter 9. Mechanobiology and Mechanotherapy in Tissue Engineering

Introduction

Cells and the Physical Environment

Mechanosensitivity of Cells

Mechanosensors, Mechanoreceptors, and Mechanosensitive Nociceptors

Mechanosignaling Pathways

Mechanobiology and Mechanotherapy

Mechanotherapy at the Molecular Level

Mechanotherapy at a Cellular Level

Mechanotherapy at the Tissue Level

Mechanotherapy for Diseases

Development of New Mechanotherapies for Tissue Engineering

Conclusion

Part 4. Smart Biomaterials Development

Chapter 10. A Biomimetic Strategy to Design Biomaterials for In Situ Tissue Regeneration

Introduction

Biomimetic Materials

Summary and Future Perspectives

List of Acronyms and Abbreviations

Chapter 11. Impact of Matrix Dynamic Properties on Stem Cell Viability

Introduction

Viability of Human Mesenchymal Stem Cells in Two Hydrogels

Stiffness and Relaxation Spectra of Two Hydrogels

Nanoscale Structural Differences Defining Fiber Dynamics

Conclusions

Glossary

List of Acronyms and Abbreviations

Chapter 12. Functionalized Polymeric Biomaterials for In Situ Tissue Regeneration

Introduction

Strategies for the Functionalized Polymeric Scaffold

Design Considerations of Functionalized Polymeric Scaffolds

In Situ Tissue Regeneration Using the Functionalized Polymeric Scaffolds

Conclusion and Future Technological Challenges

Chapter 13. Tissue-Derived Matrices

Introduction

Composition of the Extracellular Matrix

Functions of Native Extracellular Matrix

Tissue-Derived Matrices for Tissue Engineering

Current Clinical Applications for Tissue-Derived Matrices

Future Directions for Tissue-Derived Matrices

Conclusion

Glossary

List of Acronyms and Abbreviations

Part 5. Tissue-Specific Applications

Chapter 14. Synovial Joint: In Situ Regeneration of Osteochondral and Fibrocartilaginous Tissues by Homing of Endogenous Cells

Introduction

Current Treatments and Biologically Based Approaches

Regeneration of Synovial Joints by Endogenous Stem/Progenitor Cell Homing

Summary and Perspectives

Chapter 15. Bioengineered Strategies for Tendon Regeneration

Introduction

Biological Structure and Extracellular Matrix Role, Mechanical Demands, and Bioactive Molecules in Tendon Tissue

Integrated Approaches Toward Tendon Repair

Conclusions and Future Perspectives

List of Acronyms and Abbreviations

Chapter 16. In Situ Volumetric Muscle Repair

Introduction

Basic Components for In Situ Muscle Regeneration

Various Applications of Volumetric Muscle Regeneration In Situ

Leg Muscle Regeneration

Diaphragm Regeneration

Abdominal Muscle Regeneration

Conclusion and Future Perspectives

Chapter 17. Mending the Heart Through In Situ Cardiac Regeneration

Introduction

Intrinsic Regenerative Capacity of the Mammalian Heart

Systemic and Resident Cardiac Stem or Progenitor Cells

Protein Ligands for Inducing Cardiac Regeneration

Protein Delivery Systems for In Situ Cardiac Regeneration

Genetically Altering the In Situ Regeneration Capacity of the Heart

Role of MicroRNAs in Cardiac Regeneration

Direct In Situ Epigenetic Reprogramming of Nonmyocytes Into Cardiomyocytes

Conclusions

Chapter 18. Skin Wound Healing: Skin Regeneration With Pharmacological Mobilized Stem Cells

Introduction

Bone Marrow and Skin

Bone Marrow-Derived Cell Mobilization After Injury

Drugs in Mobilization of Endogenous Stem Cells

Synergy

Mechanisms

Conclusion

Chapter 19. In Situ Renal Regeneration

Introduction

In Situ Renal Regeneration: Strategy

Stem Cells Contribute to Renal Regeneration

Summary and Further Directions

Chapter 20. Regulatory Aspects: Regulation of Cell-Free Biomaterial Implants

Introduction

Medical Devices

Regulatory Scope

Bench and Laboratory Testing

Biological Evaluation: Biocompatibility

Preclinical Studies

Clinical Investigation

Conclusion

Chapter 21. Business Perspective: Case Study: Commercialized Cell-Free Cardiovascular Implant

Introduction

Product and Market Dynamics

Cost and Complexity of Getting a Highly Technical In Situ Scaffold to Market

Changing Dynamics of Healthcare

Conclusion and View to the Future

Index

Dedication

This book is dedicated to Jong Hyun Lee, Myung Hee Park, Bae Hyun Choi, Soon Jin Jeong, and Jin San Choi

Sang Jin Lee

This book is dedicated to Yook-IL, Kyung Whan, Kyung Jin, and Kyung Min

James J. Yoo

This book is dedicated to Katherine, Christopher, and Zachary

Anthony Atala

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1800, San Diego, CA 92101-4495, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2016 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

ISBN: 978-0-12-802225-2

For information on all Academic Press publications visit our website at http://www.elsevier.com/

Publisher: Mica Haley

Acquisition Editor: Mica Haley

Editorial Project Manager: Lisa Eppich

Production Project Manager: Lucía Pérez

Designer: Victoria Pearson

Typeset by TNQ Books and Journals

List of Contributors

Ahmed Abdelbaset-Ismail,     Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, KY, United States

Julie Allickson,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Feras Alshomer,     Division of Surgery and Interventional Science, University College London, London, United Kingdom

Noaf Salah Ali AlWahab,     Biomedical Engineering Department, Khalifa University, Abu Dhabi, United Arab Emirates

Antony Atala,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Alexander Baume,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Selwa Mokhtar Boularaoui,     Biomedical Engineering Department, Khalifa University, Abu Dhabi, United Arab Emirates

Nicolas Christoforou

Biomedical Engineering Department, Khalifa University, Abu Dhabi, United Arab Emirates

Biomedical Engineering Department, Duke University, Durham, NC, United States

Manuela E. Gomes,     3B’s Research Group, Department of Polymer Engineering, University of Minho, Guimarães, Portugal

Ana I. Gonçalves,     3B’s Research Group, Department of Polymer Engineering, University of Minho, Guimarães, Portugal

Hyun Sook Hong,     East-West Medical Research Institute, Kyung Hee University, Seoul, Korea

John D. Jackson,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Katherine A. Joyner,     Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, United States

Deepak M. Kalaskar,     Division of Surgery and Interventional Science, University College London, London, United Kingdom

Ji Hyun Kim,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Moon Suk Kim,     Department of Molecular Science and Technology, Ajou University, Suwon, Korea

Na Jung Kim,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Suna Kim,     Department of Genetic Engineering, Graduate School of Biotechnology, Kyung Hee University, Yong In, Korea

In Kap Ko,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Byron Lambert,     Abbott Vascular, Santa Clara, CA, United States

Bo Keun Lee,     Department of Molecular Science and Technology, Ajou University, Suwon, Korea

Chang H. Lee,     Regenerative Engineering Laboratory, Columbia University Medical Center, New York, NY, United States

Sang Jin Lee,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Yuqi Li,     Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, United States

Baisong Lu,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Ashwin Nair,     Bioengineering Department, University of Texas at Arlington, Arlington, TX, United States

Rei Ogawa,     Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan

Harald C. Ott,     Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, United States

Seung Hun Park,     Department of Molecular Science and Technology, Ajou University, Suwon, Korea

Richard Payne,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

T. Konrad Rajab,     Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, United States

Richard Rapoza,     Abbott Vascular, Santa Clara, CA, United States

Mariusz Z. Ratajczak,     Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, KY, United States

Rui L. Reis,     3B’s Research Group, Department of Polymer Engineering, University of Minho, Guimarães, Portugal

Márcia T. Rodrigues,     3B’s Research Group, Department of Polymer Engineering, University of Minho, Guimarães, Portugal

Lindsey E. Shapiro,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Alexander Sheehy,     Abbott Vascular, Santa Clara, CA, United States

Youngsook Son

Department of Genetic Engineering, Graduate School of Biotechnology, Kyung Hee University, Yong In, Korea

East-West Medical Research Institute, Kyung Hee University, Seoul, Korea

Joseph P. Stains,     Department of Orthopedics, University of Maryland, Baltimore, MD, United States

Zhaoli Sun,     Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

Liping Tang,     Bioengineering Department, University of Texas at Arlington, Arlington, TX, United States

Marc B. Taraban,     Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, United States

Solaiman Tarafder,     Regenerative Engineering Laboratory, Columbia University Medical Center, New York, NY, United States

Jeremy Choon Meng Teo,     Biomedical Engineering Department, Khalifa University, Abu Dhabi, United Arab Emirates

Hung-Jen Wang,     Division of Urology, Chang Gung Memorial Hospital, Kaohsiung County, Taiwan

George M. Williams,     Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

James J. Yoo,     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Yihua B. Yu,     Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, United States

Nan Zhang

National Institutes for Health, Bethesda, MD, United States

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Preface

Over the past few decades, cell-based therapies have become a treatment option for repairing or replacing damaged tissues and organs. However, development of cell-based therapies using a stem- or tissue-specific cell source presents substantial complexity for clinical use, and these include tissue harvest and cell isolation and expansion ex vivo. To simplify this process, researchers have sought for a means to avoid ex vivo cell manipulation, thus saving time, effort, and resources. Recent studies show that endogenous tissue-specific stem/progenitor cells can be utilized by controlling the host microenvironment, and that if given the proper biological cues, these cells could be guided to differentiate into specific cell lineages. More importantly, the differentiated tissue-specific cells, combined with biomaterials or artificial microenvironments, can be effectively integrated with the host tissue for structural and functional tissue restoration in situ. To this end, in situ tissue regeneration aims to take advantage of the body’s own regenerating capacity to activate endogenous stem cells or tissue-specific progenitors for tissue repair.

This book provides the most recent development strategies for in situ tissue regeneration in terms of mechanisms of host cell recruitment, cell sourcing, and cellular and molecular roles involved with cell differentiation, navigational cues and niche signals, and tissue-specific smart biomaterial systems, from the perspective of tissue engineering and regenerative medicine. This book is divided into four parts: (1) endogenous cell sources, (2) biochemical and physical cues, (3) smart biomaterial development, and (4) tissue-specific applications. We believe that the in situ tissue regeneration strategy has the potential to accelerate research and clinical translation of tissue engineering and regenerative medicine applications.

The editors acknowledge and extend our sincere gratitude to the experts who generously devoted valuable time and effort to share their knowledge and experience to this book. The professional support of the editorial and production team at Elsevier is also appreciated. We hope that this book will encourage readers to investigate the new paradigms in tissue engineering and regenerative medicine research.

Sang Jin Lee

James J. Yoo

Anthony Atala

Part 1

Introduction

Outline

Chapter 1. Fundamentals of In Situ Tissue Regeneration

Chapter 1

Fundamentals of In Situ Tissue Regeneration

S.J. Lee, J.J. Yoo,  and A. Atala     Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Abstract

The aim of in situ tissue regeneration is to take advantage of the body's own regenerating capacity by utilizing the host's ability to mobilize endogenous stem cells to the site of injury for tissue repair. For example, when a smart biomaterial scaffold combined with both biochemical and physical cues is implanted, the functionalized scaffold induces the recruitment of tissue-specific stem/progenitor cells and drives differentiation of these cells into targeted cell types for tissue regeneration. This approach relies on the development of a target-specific biomaterial scaffolding system that can effectively control the host microenvironment and mobilize host stem/progenitor cells to a targeted site of the injured tissues or organs. An appropriate microenvironment provided by implanted scaffolds would facilitate recruitment of host cells that can be guided to regenerate structural and functional tissues.

Keywords

Bioactive molecules; Biomaterials; In situ tissue regeneration; Regenerative medicine; Stem cells; Tissue engineering

Chapter Outline

Introduction

Strategy: In Situ Tissue Regeneration

Design Considerations: Biomaterial Scaffolds

Applications of In Situ Tissue Regeneration

Conclusion and Future Directions

List of Acronyms and Abbreviations

Acknowledgments

References

Introduction

One of the strategies in tissue engineering involves the use of biomaterial scaffolds made by naturally derived materials or synthetic polymers that provide a 3-D architecture and structural support with or without cells [1–3]. This strategy is dictated by the implantable tissue constructs and the availability of suitable cells, which allow the production of new extracellular matrix (ECM), resembling that of the native tissue to regenerate the injured tissues or organs. Using this approach, numerous preclinical and clinical studies performed in different tissue systems have shown to be effective in tissue repair or regeneration [4–8].

Although this strategy has made considerable advancements, the cell-based therapeutic approaches have proved to be limited by the donor tissue availability. Harvesting autologous tissue to obtain cells is often constrained by the anatomical access limitations and associated with donor site morbidity [9,10]. Allogeneic and xenogeneic cell sources, on the other hand, present risks of inducing immunologic responses due to genetic differences and potential bacterial and viral transmission from the donor to the host. Furthermore, this approach requires cell isolation and expansion, which involves labor-intensive cell manipulation [11]. An alternative cell source is the use of stem or progenitor cells; however, this approach also necessitates ex vivo procedures such as cell isolation, expansion, and/or differentiation of desired cell lineages and may result in loss of cellular function during expansion [12].

Figure 1.1  Schematic illustration of (A) strategy of in situ tissue regeneration and (B) interactions between endogenous stem cells and biomaterial scaffold. Stem cell fate in a particular microenvironment is regulated by intricate reciprocal molecular interactions with its surroundings.

Advanced strategies in tissue engineering and regenerative medicine have introduced the concept of recruiting host stem cell/progenitor cells to a target site of interest for in situ tissue regeneration 13–17]. The principle of in situ tissue regeneration is to take advantage of the body’s own regenerative capability by utilizing endogenous stem cells or tissue-specific progenitor cells at the site of injury. This approach provides a more efficient means of therapy by eliminating ex vivo cell manipulation. Fig. 1.1 shows a strategy of in situ tissue regeneration. For instance, when scaffolds encapsulated with bioactive molecules are implanted, sustained release of these bioactive molecules unlocks the body’s own regenerating capacity. In turn, this induces recruitment of stem/progenitor cells, drives differentiation of these cells into targeted cell types, and participates in the regeneration of functional tissues. This chapter reviews the recent development of strategies for in situ tissue regeneration, in terms of mechanism of recruitment, cell sources, cellular and molecular roles in cell differentiation, navigational cues and niche signals, and tissue-specific scaffolding systems from the perspective of regenerative medicine and tissue engineering.

Strategy: In Situ Tissue Regeneration

Stem cells, whether derived from embryos, fetuses, or adults, possess an enormous capacity for the next frontier of tissue engineering and regenerative medicine. This is due to their remarkable potential to develop into many different tissues or organs in the body with specialized functions. Given their unique regenerative capabilities, stem cells offer new potentials for treating a broad range of diseases, such as diabetes and heart disease [18,19]. Because of the significant role of stem cells in the regenerative process, a readily available population of stem cells that are highly renewable and have an extensive ability to differentiate is critical for clinical success.

Due to the ethical concerns involved with the use of embryonic stem cells, adult stem cells have increasingly gained attention. Adult stem cells are undifferentiated cells found in almost every tissue or organ, which can self-renew and differentiate into tissue-specific cell types. Their primary role is to maintain and repair tissue in which they are found. The stem cells reside in a specialized microenvironment called stem cell niche. Tissue-specific stem cells remain quiescent for relatively long periods of time until they are activated by a need for tissue maintenance or by disease or tissue injury. The presence of an underlying regenerative mechanism in the form of tissue-specific stem or progenitor cells suggests that there could be a potential opportunity to bias the host response toward repair and reconstruction of tissue defects.

Indeed, it has been widely accepted that almost every tissue in the body contains various types of stem or progenitor cells, including brain, liver, circulating blood, heart, skin, fat, kidney, and muscle [20–26]. It would seem that these premature cells are part of underlying regenerative machinery that is responsible for daily maintenance activities, including repair of normal tissue wear and tear, as well as small injuries. However, when extensive tissue damage occurs and large tissue defects are present, the regenerative response is overwhelmed, and an immune-based reparative response takes over to maintain some level of function. While the immediate problem may be mitigated by these reparative processes, responses such as inflammation, which results in uncontrolled collagen deposition and fibrosis, are undesirable because they can lead to further complications and severe deficits in tissue and organ functionality. Therefore current research efforts have focused on the improvement of the regenerative capability by controlling the host microenvironment and stem cell mobilization for in situ tissue regeneration [16].

The concept of in situ tissue regeneration occurs via the recruitment of host stem cells into an injured tissue or other target niche. Currently, various functionalized biomaterial scaffolds have been used for the reconstruction of a large tissue defect with functional recovery. From a biomaterials perspective, placing a biomaterial in the in vivo microenvironment requires injection, insertion, or surgical implantation, all of which injure the tissues or organs involved. In such instances, various reconstructive measures are necessary to restore functionality of the affected tissues or organs. However, it is well known that a biomaterial implant will become populated with host cells that ultimately result in scar tissue. The host cell infiltrate has been assumed to be inflammatory and fibroblastic, as indirect evidence (ie, the presence of collagen) has suggested that fibroblasts are the predominant cell population present after the initial inflammation has subsided.

Even though inflammatory response and foreign body reaction have been well identified, the cell types that infiltrate the biomaterial have not been fully identified. Therefore the possibility of utilizing the body’s biologic and environmental resources in situ for tissue regeneration has been investigated. As an initial step, the recruitment of host stem/progenitor cells into an implanted scaffold through the tissue repairing process has been examined. In our previous study [13], poly(glycolic acid) (PGA) nonwoven scaffold, a widely employed biocompatible, biodegradable, and implantable biomaterial, was used in a simple approach to address this dogma. The implant is highly porous and is designed to increase diffusion and accommodate host cell infiltrates. The results showed that the number of host cells continued to increase up to 3  weeks after implantation and began to decrease thereafter as collagen accumulates and fills the pores of the implanted scaffold. This is consistent with the normal inflammatory response seen in many tissue systems. However, we found that a small proportion of the infiltrated host cells within the biomaterial implants have multilineage potential (Fig. 1.2A) [13]. These results indicate that some of the host stem cells that can be mobilized into a biomaterial are multipotent, and given an optimal microenvironment, they can differentiate into specific cell types needed for functional regeneration at the implant site. One major concern is how sufficient stem cell populations can be migrated into the implanted scaffold, as the number of adult stem cells in the body is generally too low to have a significant effect on tissue regeneration in many cases. In this regard, we demonstrated effective recruitment of host stem cells into an implanted scaffold using a novel combined delivery system consisting of systemic injection of substance P and local release of stromal cell-derived factor-1α (SDF-1α) from the implanted scaffold (Fig. 1.2B) [16].

Based on these findings, a desirable paradigm in which a target-specific biomaterial system can be universally applied, without the need for ex vivo cell manipulation, may be attainable. Ideally, the patient’s body would supply both the source of cells and the microenvironment for terminal differentiation, provided the appropriate cues can be mediated through the biomaterial scaffold. Therefore in contrast to current modalities that focus on in vitro manipulation of cells, it may be possible to control tissue morphogenesis in vivo by providing the appropriate cues to the infiltrating multipotent cells, leading to the production of functional tissues in situ.

Design Considerations: Biomaterial Scaffolds

Creation of engineered tissue constructs requires a biomaterial scaffold that serves as an artificial microenvironment and provides structural support until native tissue forms. Although the requirements for biomaterial scaffolds may be different depending on the target tissues or organs, the general functions of scaffolds that need to be fulfilled include biodegradability, biocompatibility, and temporal structural integrity. In addition, the scaffold’s internal architecture should facilitate the permeability of nutrients and neovascularization. The latter is particularly important, as this porous structure not only can provide space for the recruitment of cells to reside but also can encapsulate bioactive molecules and provide cues that enhance cell migration, proliferation, and differentiation, producing a biofunctional stem cell niche. To design a biomaterial scaffolding system for in situ tissue regeneration, it should: (1) minimize foreign body reaction and fibrosis; (2) utilize host microenvironment for activating/recruiting host stem/progenitor cells; and (3) control tissue-specific cell differentiation within the target tissue of interest.

As an initial step, sufficient numbers of adjacent stem cells must be recruited into the implanted scaffold for efficient and effective tissue regeneration. However, the number of stem cells present in the body is limited. Thus, several research teams have investigated chemotaxis of circulating mesenchymal stem cells (MSCs) using various chemokines. The interaction with chemokine and chemokine receptor induces a cellular reaction in response to a specific chemokine and β-actin filament rearrangement (CXCL12). The CXC chemokine, SDF-1α (CXCL12), shows a close relationship with cell survival, migration, proliferation, and differentiation of host stem cell populations, including hematopoietic stem cells, tissue-specific progenitor cells, and MSCs. In addition, it is reported that MSCs respond in vivo to other bioactive molecules such as hepatocyte growth factor (HGF), matrix metalloproteinase-2 [27], galanin [28], and monocyte chemotactic protein-3 [29]. More directly, the sustained delivery of chemotactic factors, such as SDF-1α, using advanced release technology to drive endogenous stem cell recruitment to a tissue defect region represents a potentially novel approach to regeneration, eg, the encapsulation of these putative bioactive molecules into biodegradable polymeric scaffolds with sustained release kinetics. Furthermore, several research studies have demonstrated that delivery of exogenous SDF-1α to the myocardium prolongs the presence of SDF-1α after infarction, augmenting stem cell recruitment and improving cardiac function [30–33].

Figure 1.2  (A) The infiltrating cells (Sca-1 positive) that were induced into different cell lineages under specific conditions demonstrated the expression of their phenotypic and functional characteristics: (a) infiltrating host cells, (b) osteogenic differentiation, (c) myogenic differentiation, (d) adipogenic differentiation, and (e) endothelial differentiation as confirmed by specific marker expression. (Reproduced with permission from Lee SJ, Van Dyke M, Atala A, Yoo JJ. Host cell mobilization for in situ tissue regeneration. Rejuvenation Res 2008;11:747–56.) (B) Numbers of the recruited MSC-like cells: (a) CD29 + CD45 − cells and (b) CD146 + α-SMA + cells. (Reproduced with permission from Ko IK, Ju YM, Chen T, Atala A, Yoo JJ, Lee SJ. Combined systemic and local delivery of stem cell inducing/recruiting factors for in situ tissue regeneration. FASEB J 2011;26:158–68.)

Bioactive molecules, including growth factors, cytokines, small molecules, and genes, for in situ tissue regeneration play an important role in the control of the microenvironment in vivo [15]. Chemotactic signals from bioactive molecules are responsible for directed cell migration. An anatomic destination is identified according to a certain concentration gradient of chemicals produced in the injured sites in their microenvironment. Therefore one of the significant criteria for developing biomaterial scaffolding systems, especially for in situ tissue regeneration purposes, is to deliver bioactive molecules and regulatory signals in a precise temporal and spatial manner [34]. Initially, it is critical to efficiently induce and direct recruitment of host stem cells to the targeted sites. To achieve this, identifying and understanding the roles of bioactive molecules that initiate the recruiting response of the cells is required. Ideal delivery of bioactive molecules requires sustained release to maintain effective concentrations in a local microenvironment. Additionally, it has been demonstrated that multiple factors need to be delivered to a target application due to the complexity of the microenvironment. Mooney et al. suggested a multiple protein delivery system for accelerating vascularization and tissue formation, as the development of tissues and organs is typically driven by the action of a number of growth factors [35]. They reported a new polymeric system that allows for the tissue-specific delivery of two or more growth factors, with controlled dose and rate of delivery. Controlling sustained release of bioactive molecules with different release kinetics enables effective tissue regeneration. Likewise, a recent study shows various methods of sustained release of bioactive molecules over time [36]. Multiple sustained release mimics actual in vivo tissue regeneration, and it contributes to effective and rapid tissue regeneration. In a recent study, a gelatin-based scaffold was delivered in vivo with chemical conjugations of four different bioactive molecules: vascular endothelial growth factor (VEGF), angiopoietin-1, keratinocyte growth factor (KGF), and platelet-derived growth factor-BB (PDGF-BB). This combined delivery of multiple bioactive molecules resulted in an increase in angiogenesis with a potential for enhanced tissue regeneration [37]. Another study in skeletal muscle regeneration shows effective and functional skeletal muscle regeneration using alginate, which simultaneously released insulin-like growth factor-1 (IGF-1) and VEGF [38]. This study is important because in addition to angiogenesis, a functional skeletal muscle tissue was created with activation of muscle satellite cells.

The mechanical and molecular information coded within the extracellular milieu is guiding the development of a new generation of biomaterials for future tissue regeneration. To this end, ECM-mimicking biomaterials may provide not only structural components for supporting cells but also contain a reservoir of cell-signaling motifs and sequestered growth factors that guide cellular anchorage and behavior, inspiring multiple examples of biomimetic design for biomaterial scaffolds. In vascular research, for example, the presence of endothelium-derived macromolecules or their cell interacting domains onto vascular grafts can mimic features of the ECM and thereby assist specific cell adhesion and promote endothelialization [39].

Another consideration for in situ regeneration is to provide cell attachment sites on the scaffold in conjunction with the release of bioactive molecules involved with target cell recruitment. One ECM peptide sequence that influences cell adhesion behavior is the integrin binding arginine–glycine–aspartic acid (RGD) sequence [40–47]. Together with the integrins, the cell surface receptors that recognize the sequence of various proteins, RGD constitutes a major recognition system for cell adhesion. The RGD motif may also enhance the recruitment and activation of endoneurial phagocytes (ie, phagocytes residing in Lymnaea’s nerves) in the injury response of the nervous system of the pond snail Lymnaea stagnalis and affect nerve regeneration [48]. In an in vitro study, a designer self-assembling peptide scaffold developed by Horii et al. significantly stimulated cell migration into the 3-D scaffold, suggesting that it would be possible to apply suitable and active biological scaffolds to stimulate and promote host stem cell recruitment, differentiation, and regeneration of tissues without introducing any foreign cells [49].

Cell–biomaterial interactions continue to be a principal source of inspiration for biomaterial functionalization and thus play a very important role in future cell recruiting device design [50]. This is a dynamic and rapidly evolving field that has gained considerable attention as a means of increasing scaffold potency and to improve their biological functionality [51]. Current research has identified many peptides/proteins, various factors, and numerous techniques that could be used for the functionalization of biomaterials. New biomaterials can adapt to the surrounding microenvironment and orchestrate the transport of ions, bioactive molecules, and information transfer between cells and their microenvironment [49,52–55]. However, less is known about how such biomaterials influence and control cell function, how much extrinsic physiochemical information is required to mobilize host stem cells into regenerating a complex tissue, and specifically, taking a combination of clinical performance, marketing, and cost-effectiveness into consideration, what minimum level of biomaterial complexity is required for a given task [50]. There is an ever-increasing demand for biomaterials that can match both the mechanical and biological properties of real tissue matrix, support vascularization, and recreate nanoscale topographical and cell-specific biochemical cues [56].

Applications of In Situ Tissue Regeneration

The concept of in situ tissue regeneration has been well studied and documented in bone regeneration. The required property of biomaterial scaffolds to ensure successful treatment of bony defects is the temporary mechanical load bearing within the tissue defects. Moreover, it should minimize immune and/or inflammatory response. The biomaterials widely used for this purpose include calcium phosphate, calcium sulfate, and hydroxyapatite. Since native bone tissue consists of large amounts of such materials, they have been considered as the major component of scaffold material for bone tissue regeneration due to their chemical and crystal resemblance to the mineral phase of bone, demonstrating excellent biocompatibility and osteoconductivity [57]. As bioactive molecules for bone regeneration, bone morphogenetic protein-2 (BMP-2) [58–60] and basic fibroblast growth factor (bFGF) [61] are common and therefore vital growth factors that are introduced into the bone scaffolds [62–64]. Scaffolds made of natural polymers such as alginate, fibrin, or gelatin and synthetic biodegradable polymers such as polylactide (PLA) and poly(lactide-co-glycolide) (PLGA) incorporated with bioactive molecules alone, or in combination with calcium phosphate and/or hydroxyapatite, have been shown to be osteoinductive and osteoconductive. As such, these scaffolding systems have shown an ability to stimulate and induce neighboring bone marrow MSCs and enhance in situ bone tissue formation.

When injured, the success rate of cartilage regeneration is low compared to other types of tissues, which can lead to joint problems such as severe arthritis. In early studies, in vitro cartilage production from chondrocytes and specialized scaffolding systems has shown success. However, when the engineered cartilage was implanted, serious compatibility issues were noted in vivo. Recently, Erggelet et al. demonstrated the regeneration of cartilage using cell-free biomaterial scaffolds. They developed a biomaterial construct composed of PLGA scaffold incorporated with plasma and hyaluronic acid (HA) and implanted into a cartilage microfracture injury site [65]. The result showed that the implanted constructs induced the migration of bone marrow MSCs and the formation of neocartilage tissue. Mao and his team also demonstrated that the entire articular surface of the synovial joint can regenerate without cell transplantation using 3-D poly(ε-caprolactone) and hydroxyapatite composites fabricated by solid free-form technique. These fabricated scaffolds were coated with transforming growth factor β3 prior to implantation. This was shown to be effective in regenerating cartilage tissue by recruiting host stem cells to the site of implantation [66].

Loss of a large amount of skeletal muscle mass often results in incomplete recovery, with the development of scar tissue. If an injury is not properly treated, it will likely cause skeletal muscle weakness and atrophy [67]. As the target cell sources for in situ muscle regeneration, muscle satellite cells primarily play a significant role in muscle regeneration, owing to their self-renewal capabilities and muscle-specific differentiation [68,69]. Besides muscle satellite cells, several populations of other stem cells, such as muscle-derived stem cells (MDSCs) [70,71], pericytes [72], muscle resident macrophages [73], and bone marrow-derived MSCs [74] have been used in engineering muscle tissue, as they are closely involved in the muscle regeneration process. The roles of these cell populations are critical for efficient muscle regeneration by maturing blood vessels, secreting trophic factors, and reducing fibrotic tissue formation [71].

A novel approach that relies on the body’s ability to repair itself has been developed by utilizing host stem cell recruitment and control of cell fate. This approach is based on the release of tissue-specific stem cell stimulating factors to utilize host stem cells, followed by effective tissue regeneration [38]. In our previous work [14], we demonstrated that host myogenic cells, expressing muscle satellite/progenitor cell markers, can be mobilized into biomaterial scaffolds and then differentiated to myogenic cells for in situ muscle regeneration. Mooney’s team has also developed an injectable system based on alginate material that is able to deliver dual growth factors, IGF-1 and VEGF, for the enhancement of functional muscle regeneration. IGF-1 induces satellite cell mobilization to injured muscle tissue to proliferate and differentiate, and VEGF is a primary proangiogenic factor that recruits vessel-forming stem or progenitor cells. In another study, Kin et al. implanted a collagen scaffold into a rabbit hind limb muscle injury. Twenty-four weeks posttransplantation, implants without scaffold (control group) showed severe scar tissue formation and muscle contraction, whereas the collagen-based scaffold group showed focal tissue adhesion and new muscle tissue formation [75]. This study shows that it is possible to enrich the infiltrates with tissue-specific stem/progenitor cells to control their cell fate, provided the microenvironment imparts proper signaling to the implanted scaffold. Table 1.1 lists recent therapeutic applications of the biomaterial scaffolding systems for in situ tissue regeneration. While many technologies are at the early experimental stage, several technologies have been successfully performed in preclinical animal studies with satisfactory outcomes.

Table 1.1

Recent Therapeutic Applications of Biomaterial Scaffolds for In Situ Tissue Regeneration

BMP, bone morphogenic protein; FGF, fibroblast growth factor; GDF, growth differentiation factor; HA, hyaluronic acid; HGF, hepatocyte growth factor; PEUU, polyester urethane urea; PGA, poly(glycolic acid); PLA, poly(lactic acid); PLGA, poly(lactide-co-glycolide); PP, polyprolene; SDF-1, stromal cell-derived factor 1α; SIS, small intestine submucosa; UBM, urinary bladder matrix.

Conclusion and Future Directions

The strategy of in situ tissue regeneration has become a promising approach to safer and more convenient translational tissue engineering by avoiding the need for ex vivo manipulation of autologous cell sources; therefore it holds a great promise for the future of translational medicine. To achieve successful tissue regeneration by host stem cell recruitment, it is indispensable to direct cells to the site of injury and provide the homed cells with a local microenvironment of artificial ECM where they can proliferate and differentiate. Advances in biomaterial scaffold design and engineering are converging to enable a new generation of instructive materials that bear complex information coded in their physical, biological, and chemical structures. Elucidating the molecular complexity of cell chemotaxis, identifying both the essential molecules that dictate stem cell trafficking and their dosing criteria, improving the pharmacokinetics and biodistribution of bioactive molecules released from an implanted biomaterial, and developing products tailored to different pathologies are but a few of the challenges in the design of medical devices that conduct sufficient stem cell recruitment and robust tissue regeneration, thereby improving the benefit to individuals suffering from severely injured tissues or organs. Addressing each of these issues will lead to a future medicine in which navigational cues will be delivered to the location where they are needed and only at the levels and time at which they are required, thereby creating an innovative, biologically-based generation of clinical treatments that utilize host stem cell recruitment to regenerate injured tissues or organs in situ. For a more efficient therapeutic outcome, a better understanding of the complex interactions and pathways of the molecules that are involved in the targeted tissue regeneration is necessary.

List of Acronyms and Abbreviations

Ang-1   Angiopoietin-1

bFGF   Basic fibroblast growth factor

BMP-2   Bone morphogenetic protein-2

ECM   Extracellular matrix

ESCs   Embryonic stem cells

GDF   Growth differentiation factor

HA   Hyaluronic acid

HGF   Hepatocyte growth factor

HSCs   Hematopoietic stem cells

IGF-1   Insulin-like growth factor-1

KGF   Keratinocyte growth factor

MCP-3   Monocyte chemotactic protein-3

MDSCs   Muscle-derived stem cells

MMP-2   Matrix metalloproteinase-2

MSCs   Mesenchymal stem cells

PCL   Poly(ε-caprolactone)

PDGF-BB   Platelet-derived growth factor-BB

PEUU   Polyester urethane urea

PGA   Poly(glycolic acid)

PLA   Polylactide

PLGA   Poly(lactide-co-glycolide)

PP   Polyprolene

RGD   Arginine-glycine-aspartic acid

SDF-1α   Stromal cell-derived factor-1α

SIS   Small intestine submucosa

SP   Substance P

UBM   Urinary bladder matrix

VEGF   Vascular endothelial growth factor

Acknowledgments

This work was supported in part by the Armed Forces Institute of Regenerative Medicine (W81XWH-08-2-0032) of the Department of Defense, and the Musculoskeletal Transplant Foundation (MTF).

References

[1] Atala A. Recent developments in tissue engineering and regenerative medicine. Curr Opin Pediatr. 2006;18:167–171.

[2] Atala A, Murphy S. Regenerative medicine. JAMA. 2015;313:1413–1414.

[3] Langer R. Tissue engineering. Mol Ther. 2000;1:12–15.

[4] Atala A, Bauer S.B, Soker S, Yoo J.J, Retik A.B. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006;367:1241–1246.

[5] Raya-Rivera A, Esquiliano D.R, Yoo J.J, Lopez-Bayghen E, Soker S, Atala A. Tissue-engineered autologous urethras for patients who need reconstruction: an observational study. Lancet. 2011;377:1175–1182.

[6] Raya-Rivera A.M, Esquiliano D, Fierro-Pastrana R, Lopez-Bayghen E, Valencia P, Ordorica-Flores R, et al. Tissue-engineered autologous vaginal organs in patients: a pilot cohort study. Lancet. 2014;384:329–336.

[7] Ossendorf C, Kaps C, Kreuz P.C, Burmester G.R, Sittinger M, Erggelet C. Treatment of posttraumatic and focal osteoarthritic cartilage defects of the knee with autologous polymer-based three-dimensional chondrocyte grafts: 2-year clinical results. Arthritis Res Ther. 2007;9:R41.

[8] Shin’oka T, Matsumura G, Hibino N, Naito Y, Watanabe M, Konuma T, et al. Midterm clinical result of tissue-engineered vascular autografts seeded with autologous bone marrow cells. J Thorac Cardiovasc Surg. 2005;129:1330–1338.

[9] Burg K.J, Porter S, Kellam J.F. Biomaterial developments for bone tissue engineering. Biomaterials. 2000;21:2347–2359.

[10] Younger E.M, Chapman M.W. Morbidity at bone graft donor sites. J Orthop Trauma. 1989;3:192–195.

[11] Langer R. Biomaterials in drug delivery and tissue engineering: one laboratory’s experience. Acc Chem Res. 2000;33:94–101.

[12] Guillot P.V, Cui W, Fisk N.M, Polak D.J. Stem cell differentiation and expansion for clinical applications of tissue engineering. J Cell Mol Med. 2007;11:935–944.

[13] Lee S.J, Van Dyke M, Atala A, Yoo J.J. Host cell mobilization for in situ tissue regeneration. Rejuvenation Res. 2008;11:747–756.

[14] Ju Y.M, Atala A, Yoo J.J, Lee S.J. In situ regeneration of skeletal muscle tissue through host cell recruitment. Acta Biomater. 2014;10:4332–4339.

[15] Ko I.K, Lee S.J, Atala A, Yoo J.J. In situ tissue regeneration through host stem cell recruitment. Exp Mol Med. 2013;45:e57.

[16] Ko I.K, Ju Y.M, Chen T, Atala A, Yoo J.J, Lee S.J. Combined systemic and local delivery of stem cell inducing/recruiting factors for in situ tissue regeneration. FASEB J. 2011;26:158–168.

[17] Zhao J, Zhang N, Prestwich G.D, Wen X. Recruitment of endogenous stem cells for tissue repair. Macromol Biosci. 2008;8:836–842.

[18] Wong S.P, Rowley J.E, Redpath A.N, Tilman J.D, Fellous T.G, Johnson J.R. Pericytes, mesenchymal stem cells and their contributions to tissue repair. Pharmacol Ther. 2015;151:107–120.

[19] Joo S, Ko I.K, Atala A, Yoo J.J, Lee S.J. Amniotic fluid-derived stem cells in regenerative medicine research. Arch Pharm Res. 2012;35:271–280.

[20] Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–967.

[21] Bartsch G, Yoo J.J, De Coppi P, Siddiqui M.M, Schuch G, Pohl H.G, et al. Propagation, expansion, and multilineage differentiation of human somatic stem cells from dermal progenitors. Stem Cells Dev. 2005;14:337–348.

[22] De Ugarte D.A, Ashjian P.H, Elbarbary A, Hedrick M.H. Future of fat as raw material for tissue regeneration. Ann Plastic Surg. 2003;50:215–219.

[23] Deasy B.M, Huard J. Gene therapy and tissue engineering based on muscle-derived stem cells. Curr Opin Mol Ther. 2002;4:382–389.

[24] Gage F.H. Mammalian neural stem cells. Science. 2000;287:1433–1438.

[25] Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A, et al. CD31− but not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circulation Res. 2005;97:52–61.

[26] Zhang Y, Bai X.F, Huang C.X. Hepatic stem cells: existence and origin. World J Gastroenterol. 2003;9:201–204.

[27] Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P. MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood. 2007;109:4055–4063.

[28] Louridas M, Letourneau S, Lautatzis M.E, Vrontakis M. Galanin is highly expressed in bone marrow mesenchymal stem cells and facilitates migration of cells both in vitro and in vivo. Biochem Biophys Res Commun. 2009;390:867–871.

[29] Schenk S, Mal N, Finan A, Zhang M, Kiedrowski M, Popovic Z, et al. Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor. Stem Cells. 2007;25:245–251.

[30] Zaruba M.M, Theiss H.D, Vallaster M, Mehl U, Brunner S, David R, et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell. 2009;4:313–323.

[31] Chen F.M, Ma Z.W, Wang Q.T, Wu Z.F. Gene delivery for periodontal tissue engineering: current knowledge – future possibilities. Curr Gene Ther. 2009;9:248–266.

[32] Zhang G, Nakamura Y, Wang X, Hu Q, Suggs L.J, Zhang J. Controlled release of stromal cell-derived factor-1 alpha in situ increases c-kit+ cell homing to the infarcted heart. Tissue Eng. 2007;13:2063–2071.

[33] Sasaki T, Fukazawa R, Ogawa S, Kanno S, Nitta T, Ochi M, et al. Stromal cell-derived factor-1alpha improves infarcted heart function through angiogenesis in mice. Pediatr Int. 2007;49:966–971.

[34] Lutolf M.P, Gilbert P.M, Blau H.M. Designing materials to direct stem-cell fate. Nature. 2009;462:433–441.

[35] Richardson T.P, Peters M.C, Ennett A.B, Mooney D.J. Polymeric system for dual growth factor delivery. Nat Biotechnol. 2001;19:1029–1034.

[36] Chen F.M, An Y, Zhang R, Zhang M. New insights into and novel applications of release technology for periodontal reconstructive therapies. J Control Release. 2011;149:92–110.

[37] Elia R, Fuegy P.W, VanDelden A, Firpo M.A, Prestwich G.D, Peattie R.A. Stimulation of in vivo angiogenesis by in situ crosslinked, dual growth factor-loaded, glycosaminoglycan hydrogels. Biomaterials. 2010;31:4630–4638.

[38] Borselli C, Storrie H, Benesch-Lee F, Shvartsman D, Cezar C, Lichtman J.W, et al. Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors. Proc Natl Acad Sci USA. 2010;107:3287–3292.

[39] Lutolf M.P, Hubbell J.A. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol. 2005;23:47–55.

[40] Benoit D.S, Anseth K.S. The effect on osteoblast function of colocalized RGD and PHSRN epitopes on PEG surfaces. Biomaterials. 2005;26:5209–5220.

[41] Fittkau M.H, Zilla P, Bezuidenhout D, Lutolf M.P, Human P, Hubbell J.A, et al. The selective modulation of endothelial cell mobility on RGD peptide containing surfaces by YIGSR peptides. Biomaterials. 2005;26:167–174.

[42] Kurihara H, Nagamune T. Cell adhesion ability of artificial extracellular matrix proteins containing a long repetitive Arg-Gly-Asp sequence. J Biosci Bioeng. 2005;100:82–87.

[43] Marletta G, Ciapetti G, Satriano C, Pagani S, Baldini N. The effect of irradiation modification and RGD sequence adsorption on the response of human osteoblasts to polycaprolactone. Biomaterials. 2005;26:4793–4804.

[44] Martino M.M, Mochizuki M, Rothenfluh D.A, Rempel S.A, Hubbell J.A, Barker T.H. Controlling integrin specificity and stem cell differentiation in 2D and 3D environments through regulation of fibronectin domain stability. Biomaterials. 2009;30:1089–1097.

[45] Oharazawa H, Ibaraki N, Ohara K, Reddy V.N. Inhibitory effects of Arg-Gly-Asp (RGD) peptide on cell attachment and migration in a human lens epithelial cell line. Ophthalmic Res. 2005;37:191–196.

[46] Sagnella S, Anderson E, Sanabria N, Marchant R.E, Kottke-Marchant K. Human endothelial cell interaction with biomimetic surfactant polymers containing peptide ligands from the heparin binding domain of fibronectin. Tissue Eng. 2005;11:226–236.

[47] Salinas C.N, Anseth K.S. Decorin moieties tethered into PEG networks induce chondrogenesis of human mesenchymal stem cells. J Biomed Mater Res Part A. 2009;90:456–464.

[48] Hermann P.M, Nicol J.J, Bulloch A.G, Wildering W.C. RGD-dependent mechanisms in the endoneurial phagocyte response and axonal regeneration in the nervous system of the snail Lymnaea stagnalis. J Exp Biol. 2008;211:491–501.

[49] Horii A, Wang X, Gelain F, Zhang S. Biological designer self-assembling peptide nanofiber scaffolds significantly enhance osteoblast proliferation, differentiation and 3-D migration. PLoS One. 2007;2:e190.

[50] Dutta R.C, Dutta A.K. Cell-interactive 3D-scaffold; advances and applications. Biotechnol Adv. 2009;27:334–339.

[51] Place E.S, Evans N.D, Stevens M.M. Complexity in biomaterials for tissue engineering. Nat Mater. 2009;8:457–470.

[52] Zhang L, Rakotondradany F, Myles A.J, Fenniri H, Webster T.J. Arginine-glycine-aspartic acid modified rosette nanotube-hydrogel composites for bone tissue engineering. Biomaterials. 2009;30:1309–1320.

[53] Galler K.M, Cavender A, Yuwono V, Dong H, Shi S, Schmalz G, et al. Self-assembling peptide amphiphile nanofibers as a scaffold for dental stem cells. Tissue Eng Part A. 2008;14:2051–2058.

[54] Kim K.L, Han D.K, Park K, Song S.H, Kim J.Y, Kim J.M, et al. Enhanced dermal wound neovascularization by targeted delivery of endothelial progenitor cells using an RGD-g-PLLA scaffold. Biomaterials. 2009;30:3742–3748.

[55] Re’em T, Tsur-Gang O, Cohen S. The effect of immobilized RGD peptide in macroporous alginate scaffolds on TGFbeta1-induced chondrogenesis of human mesenchymal stem cells. Biomaterials. 2010;31:6746–6755.

[56] Chen F.M, Zhang J, Zhang M, An Y, Chen F, Wu Z.F. A review on endogenous regenerative technology in periodontal regenerative medicine. Biomaterials. 2010;31:7892–7927.

[57] Jarcho M, Kay J.F, Gumaer K.I, Doremus R.H, Drobeck H.P. Tissue, cellular and subcellular events at a bone-ceramic hydroxylapatite interface. J Bioeng. 1977;1:79–92.

[58] Chung Y.I, Ahn K.M, Jeon S.H, Lee S.Y, Lee J.H, Tae G. Enhanced bone regeneration with BMP-2 loaded functional nanoparticle-hydrogel complex. J Control Release. 2007;121:91–99.

[59] Osathanon T, Linnes M.L, Rajachar R.M, Ratner B.D, Somerman M.J, Giachelli C.M. Microporous nanofibrous fibrin-based scaffolds for bone tissue engineering. Biomaterials. 2008;29:4091–4099.

[60] Suzuki Y, Tanihara M, Suzuki K, Saitou A, Sufan W, Nishimura Y. Alginate hydrogel linked with synthetic oligopeptide derived from BMP-2 allows ectopic osteoinduction in vivo. J Biomed Mater Res. 2000;50:405–409.

[61] Kodama N, Nagata M, Tabata Y, Ozeki M, Ninomiya T, Takagi R. A local bone anabolic effect of rhFGF2-impregnated gelatin hydrogel by promoting cell proliferation and coordinating osteoblastic differentiation. Bone. 2009;44:699–707.

[62] Ginebra M.P, Traykova T, Planell J.A. Calcium phosphate cements as bone drug delivery systems: a review. J Control Release. 2006;113:102–110.

[63] Jansen J.A, Vehof J.W, Ruhe P.Q, Kroeze-Deutman H, Kuboki Y, Takita H, et al. Growth factor-loaded scaffolds for bone engineering. J Control Release. 2005;101:127–136.

[64] Seeherman H, Wozney J.M. Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev. 2005;16:329–345.

[65] Erggelet C, Endres M, Neumann K, Morawietz L, Ringe J, Haberstroh K, et al. Formation of cartilage repair tissue in articular cartilage defects pretreated with microfracture and covered with cell-free polymer-based implants. J Orthop Res. 2009;27:1353–1360.

[66] Lee C.H, Cook J.L, Mendelson A, Moioli E.K, Yao H, Mao J.J. Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study. Lancet. 2010;376:440–448.

[67] Huard J, Li Y, Fu F.H. Muscle injuries and repair: current trends in research. J Bone Joint Surg Am. 2002;84-A:822–832.

[68] Le Grand F, Rudnicki M. Satellite and stem cells in muscle growth and repair. Development. 2007;134:3953–3957.

[69] Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau H.M. Self-renewal and expansion of single transplanted muscle stem cells. Nature. 2008;456:502–506.

[70] Qu-Petersen Z, Deasy B, Jankowski R, Ikezawa M, Cummins J, Pruchnic R, et al. Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. J Cell Biol. 2002;157:851–864.

[71] Sun D, Martinez C.O, Ochoa O, Ruiz-Willhite L, Bonilla J.R, Centonze V.E, et al. Bone marrow-derived cell regulation of skeletal muscle regeneration. FASEB J. 2009;23:382–395.

[72] Crisan M, Yap S, Casteilla L, Chen C.W, Corselli M, Park T.S, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3:301–313.

[73] Polesskaya A, Seale P, Rudnicki M.A. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell. 2003;113:841–852.

[74] LaBarge M.A, Blau H.M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell. 2002;111:589–601.

[75] Kin S, Hagiwara A, Nakase Y, Kuriu Y, Nakashima S, Yoshikawa T, et al. Regeneration of skeletal muscle using in situ tissue engineering on an acellular collagen sponge scaffold in a rabbit model. ASAIO J. 2007;53:506–513.

[76] Gomez G, Korkiakoski S, Gonzalez M.M, Lansman S, Ella V, Salo T, et al. Effect of FGF and polylactide scaffolds on calvarial bone healing with growth factor on biodegradable polymer scaffolds. J Craniofac Surg. 2006;17:935–942.

[77] Woodruff M.A, Rath S.N, Susanto E, Haupt L.M, Hutmacher D.W, Nurcombe V, et al. Sustained release and osteogenic potential of heparan sulfate-doped fibrin glue scaffolds within a rat cranial model. J Mol Histol. 2007;38:425–433.

[78] Mabilleau G, Aguado E, Stancu I.C, Cincu C, Basle M.F, Chappard D. Effects of FGF-2 release from a hydrogel polymer on bone mass and microarchitecture. Biomaterials. 2008;29:1593–1600.

[79] Nakashima S, Nakamura T, Han L, Miyagawa K, Yoshikawa T, Sakakura C, et al. Experimental biliary reconstruction with an artificial bile duct using in situ tissue engineering technique. Inflamm Regen. 2007;27:579–585.

[80] Iwai S, Sawa Y, Taketani S, Torikai K, Hirakawa K, Matsuda H. Novel tissue-engineered biodegradable material for reconstruction of vascular wall. Ann Thorac Surg. 2005;80:1821–1827.

[81] Yokota T, Ichikawa H, Matsumiya G, Kuratani T, Sakaguchi T, Iwai S, et al. In situ tissue regeneration using a novel tissue-engineered, small-caliber vascular graft without cell seeding. J Thorac Cardiovasc Surg. 2008;136:900–907.

[82] Huynh T, Abraham G, Murray J, Brockbank K, Hagen P.O, Sullivan S. Remodeling of an acellular collagen graft into a physiologically responsive neovessel. Nat Biotechnol. 1999;17:1083–1086.

[83] Fujimoto K.L, Guan J, Oshima H, Sakai T, Wagner W.R. In vivo evaluation of a porous, elastic, biodegradable patch for reconstructive cardiac procedures. Ann Thorac Surg. 2007;83:648–654.

[84] Landa N, Miller L, Feinberg M.S, Holbova R, Shachar M, Freeman I, et al. Effect of injectable alginate implant on cardiac remodeling and function after recent and old infarcts in rat. Circulation. 2008;117:1388–1396.

[85] Kubo M, Imai S, Fujimiya M, Isoya E, Ando K, Mimura T, et al. Exogenous collagen-enhanced recruitment of mesenchymal stem cells during rabbit articular cartilage repair. Acta Orthop. 2007;78:845–855.

[86] Dahms S.E, Piechota H.J, Dahiya R, Gleason C.A, Hohenfellner M, Tanagho E.A. Bladder acellular matrix graft in rats: its neurophysiologic properties and mRNA expression of growth factors TGF-alpha and TGF-beta. Neurourol Urodyn. 1998;17:37–54.

[87] Urita Y, Komuro H, Chen G, Shinya M, Kaneko S, Kaneko M, et al. Regeneration of the esophagus using gastric acellular matrix: an experimental study in a rat model. Pediatr Surg Int. 2007;23:21–26.

[88] Hiraoka Y, Yamashiro H, Yasuda K, Kimura Y, Inamoto T, Tabata Y. In situ regeneration of adipose tissue in rat fat pad by combining a collagen scaffold with gelatin microspheres containing basic fibroblast growth factor. Tissue Eng. 2006;12:1475–1487.

[89] Nakahara T, Nakamura T, Kobayashi E, Inoue M, Shigeno K, Tabata Y, et al. Novel approach to regeneration of periodontal tissues based on in situ tissue engineering: effects of controlled release of basic fibroblast growth factor from a sandwich membrane. Tissue Eng. 2003;9:153–162.

[90] Herberg S, Siedler M, Pippig S, Schuetz A, Dony C, Kim C.-K, et al. Development of an injectable composite as a carrier for growth factor-enhanced periodeontal regeneration. J Clin Periodontol. 2008;35:976–984.

[91] Boucard N, Viton C, Agay D, Mari E, Roger T, Chancerelle Y, et al. The use of physical hydrogels of chitosan for skin regeneration following third-degree burns. Biomaterials. 2007;28:3478–3488.

[92] Abbushi A, Endres M, Cabraja M, Kroppenstedt S.N, Thomale U.W, Sittinger M, et al. Regeneration of intervertebral disc tissue by resorbable cell-free polyglycolic acid-based implants in a rabbit model of disc degeneration. Spine. 2008;33:1527–1532.

[93] Hori Y, Nakamura T, Matsumoto K, Kurokawa Y, Satomi S, Shimizu Y. Experimental study on in situ tissue engineering of the stomach by an acellular collagen sponge scaffold graft. ASAIO J. 2001;47:206–210.

Part 2

Endogenous Cell Sources

Outline

Chapter 2. Stem Cell Homing

Chapter 3. Immunology: Host Responses to Biomaterials

Chapter 4. Foreign Body Reaction and Stem Cell Responses

Chapter 2

Stem Cell Homing

M.Z. Ratajczak,  and A. Abdelbaset-Ismail     Stem Cell Institute, James Graham Brown Cancer Center

Abstract

Homing was initially described as a process that orchestrates the migration of posttransplantation hematopoietic stem cells (HSCs) from peripheral blood to the bone marrow microenvironment, where these cells settle into specific stem cell niches. Thus homing of HSCs to their niches precedes engraftment and the establishment of transplant-derived hematopoiesis. Homing can also be understood more broadly as the migration of non-HSC-specific areas in tissues. It is enforced by chemotactic factors released in a given microenvironment that attract migrating cells. These chemotactic factors may by peptide-based (eg, chemokines or growth factors), bioactive phosphosphingolipids [eg, sphingosine-1-phosphate (S1P) or ceramide-1-phosphate (C1P)], or extracellular nucleotides (eg, ATP or UTP). Stem cells may also respond to a Ca²+ or H+ gradient by employing calcium- or proton-sensing receptors, respectively. Homing may also be sensitized by certain factors, such as small antimicrobial cationic peptides (eg, LL-37 or β2-defensin), or modulated by certain pharmacological compounds that affect cholesterol-enriched membrane lipid raft formation.

Keywords

Adult stem cells; Ceramide-1-phosphate (C1P); Chemotaxis; CXCR4; Extracellular nucleotides; Lipid rafts; Priming phenomenon; SDF-1; Sphingosine-1-phosphate (S1P); Stem cell homing; VLA-4

Chapter Outline

Introduction

Homing of Hematopoietic Stem Cells to Bone Marrow Niches

Changes in the Bone Marrow Level of Chemoattractants for Hematopoietic Stem Cells

Homing of Nonhematopoietic Stem Cells to Damaged Organs

To Modulate Homing Gradients as a Strategy to Deliver Therapeutic Stem Cells to the Damaged Organs

Conclusions

Acknowledgments

References

Introduction

Stem cell homing is a process whereby stem cells respond to gradients of chemoattractants by migrating up these gradients and lodging within specific tissue areas [1–3]. This process was initially described for hematopoietic stem cells (HSCs), which migrate after transplantation from peripheral blood (PB) to stem cell niches located in the bone marrow (BM) microenvironment. Stem cell niches provide HSCs with the optimal microenvironment for their biological functions. In BM niches, HSCs are retained, remain quiescent, respond to external cues, and, if necessary, undergo symmetric or asymmetric cell divisions [1,4–6].

Generally, two types of stem cell niches are distinguishable in the BM microenvironment: the osteoblastic niche, located close to the trabecular bone, and the vascular niche, which is associated with the endothelium lining BM sinusoids [7–11]. It has been postulated that, while osteoblastic niches are populated by HSCs that are more quiescent, endothelial niches contain stem cells that are more advanced in the cell cycle. On the other hand, recent morphological studies on the BM microenvironment suggest that often both types of niches overlap anatomically, and it is difficult to treat them as separate niches.

The major mechanism that retains HSCs in their niches in the BM microenvironment involves interaction of the CXCR4 receptor with α-chemokine stromal-derived factor 1 (SDF-1) and the α1β4 integrin receptor (VLA-4) with vascular adhesion molecule 1 (VCAM-1) [4,5,12–22]. While CXCR4 and VLA-4 receptors are expressed on the surface of HSCs, SDF-1 and VCAM-1 are expressed on the surface of cells lining the osteoblastic and endothelial niches. Evidence has accumulated that retention of HSCs in BM is an active process that counteracts the chemotactic gradient of sphingosine-1-phosphate (S1P), which is already very steep between PB and BM under steady-state conditions and pulls these cells in the opposite direction [3,23–25].

In a broader sense of this term, homing