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2022 | Buch

Peripheral Nerve Tissue Engineering and Regeneration

herausgegeben von: Dr. James B. Phillips, David Hercher, Prof. Dr. Thomas Hausner

Verlag: Springer International Publishing

Buchreihe: Reference Series in Biomedical Engineering


Über dieses Buch

This updatable book provides an accessible informative overview of the current state of the art in nerve repair research.The introduction includes history of nerve repair research and establishes key concepts and terminology and will be followed by sections that represent the main areas of interest in the field: (1) Biomaterials, (2) Therapeutic Cells, (3) Drug, Gene and Extracellular Vesicle Therapies, (4) Research Models and (5) Clinical Translation. Each section will contain 3 - 6 chapters, capturing the full breadth of relevant technology. Bringing together diverse disciplines under one overarching theme echoes the multidisciplinary approach that underpins modern tissue engineering and regenerative medicine. Each chapter will be written in an accessible manner that will facilitate interest and understanding, providing a comprehensive single reference source. The updatable nature of the work will ensure that it can evolve to accommodate future changes and new technologies. The main readership for this work will be researchers and clinicians based in academic, industrial and healthcare settings all over the world.


The History of Nerve Repair
This brief review traces the history of peripheral nerve repair, from the nihilistic attitude of early Greek physicians, via the occasional Renaissance proponent of tension-free anastomosis of nerve stumps, and the centuries-long reluctance of most surgeons to intervene for fear of causing severe postoperative pain, to current clinical practice involving microsurgery. Although the need to treat nerve injuries sustained in battle has long been a major driver in the quest for effective treatment, the transition from empiricism to evidence-based practice has occurred relatively recently along this time line. Modern concepts of the structure of peripheral nerves and their cellular responses to traumatic injury evolved in the nineteenth century pari passu with the emergence of increasingly sophisticated microscopical and neurophysiological techniques. Defining the cellular and molecular events that occur after a nerve has been injured, whether by ischemia, crush, or transection, informs the current management of such injuries. Despite many decades of research, it is a sobering thought that functional outcomes after repair frequently remain unsatisfactory.
Susan Standring

The Peripheral Nerve Repair Environment

Blood Supply and Microcirculation of the Peripheral Nerve
The aim of this chapter is to comprehensively compile the current body of knowledge relating to the blood supply and microcirculation of the peripheral nerve. Key findings are summarized to convey to readers which important aspects have been discovered and which further studies could be of special interest. The complex anatomy of the peripheral nerve’s microcirculatory system, its physiology, and pathophysiology as well as its crucial involvement in nerve regeneration are discussed. Special emphasis is placed on the lymphatic system, the involvement of which in peripheral nerve injury and regeneration remains to be elucidated. This chapter focuses on experimental concepts and emerging techniques to deepen our understanding of the peripheral nerve vascular system, both in regard to its function and how it could be modified to enhance nerve regeneration. It concludes with an outlook on clinical applications to improve peripheral nerve (re)vascularization, ranging from vascularized nerve grafts and surgical angiogenesis to bioengineered conduits and the use of stems cells. With the help of this chapter, researchers interested in tissue-engineering will be provided with a broad fundament of knowledge, intended as an aid for the development of new approaches to improve peripheral nerve regeneration.
Cosima Prahm, Johannes Heinzel, Jonas Kolbenschlag
The Immune Response and Implications for Nerve Repair
This chapter aims to provide an overview of the host response to allografts or tissue-engineered constructs containing allogeneic cells in peripheral nerve repair, and potential approaches for promoting the survival of nerve grafts. A large body of current research aims to improve surgical approaches for nerve repair beyond that of the autograft. Potential approaches include nerve allografts, or tissue-engineered nerve constructs which could provide an unlimited source of donor tissue for nerve injury repair. This field requires an interdisciplinary approach to the design of novel therapies, and consideration of the immune response to transplants should not be overlooked. There are many benefits of including living donor cells within transplanted nerve conduits which can improve axonal guidance, vascularization, and promote the release of growth factors to increase regeneration. It is most likely that donor cells or tissues will be of allogeneic origin, with associated implications for eliciting an immune response on transplantation. The following sections provide a summary of the immune response to nerve grafts for consideration in the development of approaches to nerve repair, including some approaches currently under investigation for preventing rejection of transplants.
Victoria H. Roberton
Autonomic Nervous System Repair and Regeneration
The autonomic nervous system is a component of the peripheral nervous system involved in visceral functions and divided into three distinct components: sympathetic, parasympathetic, and enteric nervous system. All these divisions are made up of afferent and efferent fibers providing sensory input to the central nervous system and motor output through motor visceral nerves.
Similarly to the somatic nervous system, lesions affecting the autonomic nervous system are very frequent and, depending on the degree of severity, result in a complete or partial loss of functionality of the visceral organ involved. Given the anatomical location, most autonomic nerve lesions are classified as iatrogenic injuries caused by possible complications in various medical treatments, drug administration, injection, radiation, traction during preoperative patient positioning, and surgical procedures. This review provides an overview of the most frequent iatrogenic autonomic nerve lesions occurring during substantial surgical procedures, prostatectomy, hysterectomy, and heart transplantation. In addition, the main factors that influence and characterize nerve regeneration in the autonomic nervous system will be discussed and a particular focus on the importance of in vitro and ex vivo models, which allow extrapolation of important data in the study of such regeneration, will be provided. Finally, an overview of the main scientific evidence that testifies to neurogenesis in the enteric nervous system will be provided, where some changes, following several types of nerve damage and injuries, in cell signaling molecules are thought to have neurogenic properties in the gut.
Luisa Muratori, Federica Fregnan, Giacomo Carta, Stefano Geuna

Models and Evaluation of Peripheral Nerve Regeneration

Appropriate Animal Models for Translational Nerve Research
This chapter will focus on aspects to be considered when evaluating the properties of novel materials and constructs for bioartificial and tissue-engineered nerve graft repair in preclinical research. The potential for propagation of a novel nerve guide into a medical product for clinical use is significantly increased after its regeneration-supporting properties have been proven in specific and comprehensive in vitro and in vivo studies. The predictability toward clinical outcome is of outmost importance for translational research. This is why experimental investigation of novel nerve grafts should deliver results that have been comprehensively evaluated in appropriate models. Therefore, thoughtful study design is a main concern as is also publishing of conclusive results presenting novel developments eventually holding great promise and deserving the enterprise to be processed toward a clinical product. Nevertheless, comprehensive analysis will also reveal developments that are clearly less promising for various reasons, and also these results should be published in order to speed up straightforward modification of the attempt or to avoid others from wasting time, money, and human and animal resources. In the following paragraphs, considerations on the most appropriate, mainly in vivo, models for translational research in peripheral nerve repair will be presented. During this the reader will also be referred to some recently published excellent review articles that have already substantially contributed to the discussion and deserve deeper recognition from the interested reader. As in all other fields of biomedical research, careful study design should also be considered as a valuable tool to speed up the process for novel developments to achieve clinical approval for the eventual benefit of the patients.
Kirsten Haastert-Talini
Basic Nerve Histology and Histological Analyses Following Peripheral Nerve Repair and Regeneration
In peripheral nerve studies, histological analyses represent one of the most widely used and informative quality controls to demonstrate nerve tissue regeneration. These analyses require several technical procedures, and a basic knowledge of nerve histology and regeneration is needed for the correct interpretation of the histological information obtained from the experimental studies. For this reason, the aim of this chapter is to review the basic nerve histology and regeneration, as well as the technical procedures and stainings available for the assessment of nerve tissue regeneration. In this sense, some concepts and technical details of the nerve tissue fixation and processing for light and electron microscopy are comprehensively discussed. In relation to histological staining, they were reviewed according to their application in the assessment of nerve tissue regeneration, stromal remodeling, and host response following nerve repair and regeneration. Finally, the importance and main advantages offered by the quantitative analyses of nerve regeneration, mainly focused on the semithin and ultrastructural analyses, were reported.
Jesús Chato-Astrain, Óscar D. García-García, Fernando Campos, David Sánchez-Porras, Víctor Carriel
Mathematical Modeling for Nerve Repair Research
Peripheral nerve tissue engineering has great promise for growing replacement tissues to treat peripheral nerve injuries. To date, the design of replacement tissues has focused on in vitro and in vivo experiments to characterize and test the impact of a vast range of materials, cells, and other factors, with limited translation to human trials. Here we propose and discuss the use of in silico modeling as a complementary approach to inform and accelerate the design of engineered replacement tissues.
Mathematical modeling in nerve regeneration is a small research field; however, there is a rich literature in using mathematical modeling to describe a host of highly relevant underpinning mechanisms (such as neurite growth, chemical diffusion, and angiogenesis) in different contexts. These models broadly fall into three categories: continuum (or averaged), discrete (or individual), and hybrid approaches, which combine the two. The key features and potential of these modeling categories are presented alongside a decision tree for matching a specific biological problem to the appropriate modeling approach. To be predictive, it is essential that mathematical models are benchmarked against experimental data. We present tools to efficiently fit models to such data (optimization) and investigate the reliability of model predictions (sensitivity analysis). Finally, this work concludes with two demonstrative case studies on the use of mathematical modeling (one continuum, one discrete) to tackle biological and design questions in peripheral nerve injury repair.
Simão Laranjeira, Rachel Coy, Rebecca J. Shipley

Biomaterials for Peripheral Nerve Regeneration

Biomaterials and Scaffolds for Repair of the Peripheral Nervous System
Peripheral nerve injuries are a global challenge, causing long term disabilities to the patient and reducing quality of life. Such injuries are common and frequently require surgical intervention due to the complexity and significance of the injury. Autografts are the current clinical gold standard intervention, however, a major disadvantage exists with donor site morbidity and a lack of donor nerve tissue. Therefore, the use of nerve guide conduits (NGCs) is an attractive alternative approach to treat peripheral nerve injuries. Commercial NGCs are hollow tubes, and also wraps, manufactured from natural or synthetic materials. However, only modest success is reported with these devices, and therefore a need exists to create materials that are more beneficial for reinnervation, combined with more elegant methods for fabricating guidance structures. This chapter reviews current biomaterials used for peripheral nerve repair, both experimentally, clinically and commercially. We also discuss advances in the field, from hollow tube designs to those with complex structures, the use of intraluminal scaffolds, incorporation of growth factors and the use of autologous and allogenic supporting cells to improve nerve regeneration in vivo.
Caroline S. Taylor, John W. Haycock
Fibrin in Nerve Tissue Engineering
This chapter will focus on the use of fibrin for peripheral nerve repair and regeneration. Important basic aspects of fibrinogen and fibrin will be summarized to elucidate the role of fibrin in physiologic processes such as hemostasis and wound healing. The pivotal role of fibrin in nerve regeneration will be discussed in the following section, as current approaches to enhance peripheral nerve regeneration are based on our momentary understanding of the physiological process of neuronal regeneration. The main focus of this work will be on the plethora of applications, which have been developed to take advantage of and modify fibrin’s intrinsic biological properties in peripheral nerve repair and regeneration. This chapter will shed light on its use as adhesive for the repair of severed nerves and to stabilize neurorrhaphy sites in order to protect sutured nerves. Nerve conduits made from fibrin will also be discussed, as well as the multitude of applications in which fibrin serves as a carrier for neurotrophic factors and other molecules to enhance nerve regeneration in vivo and in vitro. The following pages are thought to meet the needs and expectations of both clinicians, for example, plastic surgeons, orthopedic surgeons, and neurosurgeons, as well as of basic researchers, for example, biologists. Advantageous features of fibrin from a physician’s point of view will be highlighted in addition to chemical and molecular aspects which might be of special interest for basic researchers in the laboratory. In summary, we aim to give a comprehensive overview on fibrin and its application from “bench to bedside” in translational research.
Johannes Heinzel, Matthias Gloeckel, Andreas Gruber, Philipp Heher, David Hercher
Silk Biomaterials in Peripheral Nerve Tissue Engineering
Peripheral nerve regeneration represents a major clinical challenge especially if nerve tissue must be replaced to regain function. Repair of critical size nerve defects with development of optimal nerve conduits is the subject of numerous in vitro and in vivo studies. In this regard, natural silk and silk fibroin are widely used materials for tissue engineering of peripheral nerve conduits for implantation. In this chapter, a broad overview of pathophysiological changes and parameters of nerve injuries for repair techniques to achieve nerve regeneration is presented with an emphasis on silk as a biomaterial in tissue engineering. Differences in the variety of silk sources with their individual advantages and disadvantages are discussed with a focus on nerve regeneration. Furthermore, additional components for enhancement of nerve regeneration which must be considered including extracellular matrix proteins, growth factors, peptides sequences, and cellular support to biofunctionalize silk-based nerve conduits are summarized. Finally, clinical translation using experimental in vivo models is presented.
Flavia Millesi, Tamara Weiss, Christine Radtke
Collagen Biomaterials for Nerve Tissue Engineering
Proteins in the collagen family represent some of the most versatile natural biomaterials used in neural tissue engineering. Their widespread use is mainly prompted by their favorable physicochemical properties, rich biological activity, and abundant expression in the native extracellular matrix. This chapter presents an overview of the various applications of collagen-based biomaterials developed for neural tissue engineering.
Despoina Eleftheriadou, James B. Phillips

Therapeutic Options for Peripheral Nerve Regeneration

Schwann Cells in Nerve Repair and Regeneration
After peripheral nerve injury, both Schwann cells and PNS neurons reprogram to new phenotypes that promote repair. Myelin and Remak cells generate repair Schwann cells that support neuronal survival and promote axonal regeneration. Trophic factors, cytokines, and epithelial-mesenchymal transition (EMT) genes are upregulated, myelin genes are downregulated, autophagy is activated, and the cells proliferate, elongate, and branch to form regeneration tracks. This reprogramming has features in common with injury responses in other tissues. The repair Schwann cell phenotype fades with time after injury, and in aged animals the activation of the repair phenotype is subdued. This is a key contributor to poor axonal regeneration through the distal nerve stump after long-term denervation and in aged animals. The connective and epithelial tissues of peripheral nerves are important factors in nerve homeostasis and injury, and the formation of these protective tissues is dependent on developing Schwann cells. It has become clear that among the mechanisms that control repair cells are dedicated signals, including c-Jun, Merlin, STAT3, and epigenetic mechanisms that have relatively little or no function in development. In the future, it will be important to learn more about the distinctive signalling pathways that control the performance and long-term maintenance of repair Schwann cells, since this will facilitate the search for ways to manipulate these mechanisms for promoting regeneration.
Kristjan R. Jessen, Rhona Mirsky
Therapeutic Cells and Stem Cells for Nerve Regeneration
Although there is a considerable regenerative potential in the peripheral nervous system, recovery after traumatic nerve injuries, especially in the case of severe lesions, is incomplete. Despite the recent improvements in microsurgical techniques and the development of new nerve conduits that have widened the availability of tools to achieve more successful reinnervation of the peripheral targets, the clinical outcome is often still not satisfactory. The availability of autologous Schwann cells as donor cell types is very limited and their use from allogeneic sources raises a number of questions. Therefore the use of the regeneration-promoting effect of stem cells in peripheral nerve regeneration following injuries appears to be crucial. Multi- or pluripotent stem cells with a self-renewing capacity may be taken from several sources for preclinical applications and their use proved to be very promising to induce improved morphological and functional recovery in the injured peripheral nervous system.
The future opportunities along with the pros and cons of stem cell–based therapies to improve peripheral nerve regeneration are discussed in this chapter.
Krisztián Pajer, Antal Nógrádi
Extracellular Vesicles for Nerve Regeneration
The rapidly evolving collective fields of tissue engineering and regenerative medicine (TERM) have high potential for development of new clinical therapies for treatment of peripheral nerve injuries. The positive results of experimental nerve repair strategies incorporating transplanted cells are now largely attributed to the secretion of paracrine factors, rather than cell engraftment. Extracellular vesicles (EVs), which make up part of the cell secretome, have emerged as important intercellular communicators in various biological processes. The bioactivity of EVs is mediated by their cargoes of various types of nucleic acids and proteins. In this chapter we present an overview of the biogenesis, isolation, and characterization of EVs, and describe how EVs might be useful adjuncts in TERM for peripheral nerve repair. In summary, EVs enhance axonal growth in vitro and in vivo, modulate Schwann cell function, and are highly likely to influence the neuroimmune and vascular cell reactions activated by peripheral nerve injury. Thus EVs have high potential for use as a new cell-free therapeutic approach for nerve repair.
Gustav Andersson, Paul J. Kingham
Drug Therapies for Peripheral Nerve Injuries
Following a peripheral nerve injury (PNI), neurons have the capacity to regenerate but the rate is remarkably slow. Microsurgical treatments are used to reconnect the nerve stumps following a PNI and encourage the regeneration of axons; however, there are currently no therapies available to promote the rate of this regeneration. Drug therapies available for PNI tend to focus on the resulting symptoms such as neuropathic pain, inflammation, and weakness without modifying the condition itself. Effectively designed pharmacological treatments could potentially increase the regenerative rate as well as maintain neuronal viability and improve axonal specificity to target organs. Appropriate drug agents need to target specific events following a nerve injury and advancements in understanding of the molecular and cellular cascades which follow injury could inform this. Some drugs and targets within signaling pathways have been identified, but challenges remain with clinical translation.
Melissa L. D. Rayner, Jess Healy, James B. Phillips

Clinical Aspects

Surgical Techniques in Nerve Repair
This chapter focuses on surgical strategies in nerve repair. Surgical treatment should be adapted to the type and proximity of the peripheral nerve lesion and the time interval since trauma. The gold standard for bridging a segmental nerve defect gap is still autologous interfascicular nerve grafting according to Millesi. However, sources of autologous nerve grafts are limited and therefore the use of nerve allografts and nerve conduits is discussed. If there is a loss of the proximal nerve stump and/or the calculated time interval for successful reinnervation seems to be too long, nerve transfers and end-to-side coaptation are possible treatment approaches. The main goal of our treatment is to provide a maximum of possible nerve fibers for reinnervation. This concept implies that peripheral nerve fiber transfer as the single source for reinnervation is not adequate. If possible, the nerve lesion must be explored and the reconstruction of the lesion should be part of the treatment. Muscle-tendon transfer after nerve reconstruction is an essential part of surgical strategy. Neurolysis is a procedure to decompress nerve fascicles after external compression and neural fibrotic changes. If this procedure is performed in a methodical way and the decompression of fascicles is the main goal, it is a useful therapeutic tool for all nerve compression syndromes. The importance of the gliding tissues around the nerve and their reconstruction in this type of pathology is comprehensively discussed. Finally, some basic strategies are provided for different types of brachial plexus injury, including functional free muscle transfer.
Robert Schmidhammer, Rudolf Rosenauer, Thomas Hausner
Clinical Outcome Measures Following Peripheral Nerve Repair
The Future for Assessment of the Processes and Experiences of Nerve Injury
The hope of translational medicine is to identify treatments that improve the rate and quality of neuronal recovery following peripheral nerve injuries (PNI). A major obstacle to the trial of new treatments for PNI is the absence of sensitive and responsive measures of clinical function, which are the ultimate outcome of the biological events of nerve regeneration.
The development of objective clinical measures of nerve regeneration that are sensitive, responsive, and valid is challenging for a number of reasons. The Peripheral Nervous System (PNS) allows us to have complex interactions with our surroundings (for example, the perception of pain, touch, and temperature). Developing objective measures that reflect the multimodal function of the PNS and separate it from psychological influences on that experience is difficult. Secondly, the recovery of function following PNI is dependent upon a number of biological processes at multiple levels including the end organ, the damaged nerve segments, as well as the Central Nervous System (CNS). Clinical measures that quantify these changes and relate them to the recovery of function are not well documented.
The biological process of neural regeneration is often assessed in the research arena through postmortem tissue assessment. However, the harvesting of vital nerve tissue for assessment of neural regeneration often risks the function that has been recovered. Therefore, this is not feasible when studying the biological process of regeneration in humans. This has necessitated the development of noninvasive methods to attain the same degree of assessment of biological regeneration.
In order to assess the biological mechanisms of tissue and cellular regeneration, the relationship of these processes with human clinical experiences needs to be explained. Correlating these new areas of human assessment will help establish the influence of the complex biological processes that underpin nerve regeneration on the lived experience of nerve injury.
This chapter provides an overview of the clinical, neurophysiological, and imaging assessments that can provide pre-, intra-, and postoperative measures of nerve regeneration. This will inform the development of outcome measures that have the capacity to detect a meaningful cinical response in clinical trials which aim to detemine the efficacy of new therapies for PNI.
Matthew Wilcox, Hazel Brown, Tom Quick
Regenerative Therapies for Acquired Axonal Neuropathies
Peripheral neuropathies (PN) are the most common neurodegenerative disease globally. A variety of different insults lead to PN which include diabetes, cancer chemotherapy, and infectious diseases (such as HIV, Campylobacter jejuni, and hepatitis C). The clinical signs and symptoms depend on the extent of damage to motor, sensory, and autonomic fibers as well as the pain systems. Despite this heterogeneity of etiologies, the pathogenesis of PN is confined to one of several biological mechanisms that lead to eventual axonal degeneration. These molecular mechanisms allow identification of appropriate therapeutic targets to promote regeneration and functional recovery, but so far none of these preclinical discoveries resulted in clinical success. In addition, the poor ability of regenerating axons to reach their target represents a significant challenge to the development of effective regenerative therapies. This has stimulated research into new therapeutic delivery strategies. As a result, transdermal drug delivery and gene therapy have emerged as ideal candidates to circumvent these challenges. This chapter provides an insight into how these technologies can be harnessed to maximize the benefit of regenerative therapies for acquired axonal PN.
Matthew Wilcox, Aysel Cetinkaya-Fisgin, Ahmet Höke
Rehabilitation of Nerve Injuries
Historically, surgical outcomes following peripheral nerve injury (PNI) have focused on the motor (movement and strength) and sensory losses that patients experience. Rehabilitation following nerve injury goes well beyond these empirical elements of function. Therapists recognize that functional loss resulting from a PNI is not contained to the physical manifestation of symptoms but also has a wider impact on personal and societal interactions. These patient-specific factors have been highlighted in many qualitative research studies. Understanding a patient’s experiences of recovery provides insight into what reinnervation and the resultant return of movement, muscle strength, and sensation mean to the individual. This chapter outlines factors which should be considered when constructing an individual rehabilitation program. Examples are primarily drawn from injuries to the upper extremity, but the principles of rehabilitation can be applied to most peripheral nerve injuries.
Hazel Brown, Kathryn Johnson, Suzanne Beale, Caroline Miller
Peripheral Nerve Tissue Engineering and Regeneration
herausgegeben von
Dr. James B. Phillips
David Hercher
Prof. Dr. Thomas Hausner
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