Advanced Therapies in Regenerative Medicine

The following sections are included:

• Foreword
• Preface
• Contents
• Contributing Authors

The following sections are included:

• Introduction
• iPSCs as a Substitute for hESCs
• Moral Complicity
• Informed Consent Issues
• Monitoring and Oversight
• Pluripotent into Totipotent Cells: The Re-emergence of the Embryo Issue
• Conclusion
• References

The following sections are included:

• Introduction
• Mesenchymal Stem Cells
• MSCs in Tissue Regeneration
• MSCs in Haematopoietic Stem Cell Co-Transplantation
• Conclusion
• References

The following sections are included:

• Introduction
• Stem Cells
• Stem Cell Types
• Mobilisation and Integration
• Background
• Parkinson's Disease (PD)
• Regenerative Therapy: Use of Stem Cells
• Protocols
• Medical Team for Stem Cell Treatment
• Safety in the Infusion of Stem Cells
• Results
• Conclusion
• References

The following sections are included:

• History and Evolution
• Composition of Fat Tissue
• Adipose-Derived Stem Cells (ASC)
• Growth Factors
• Lipoaspirate Supplementation of Growth Factors
• Technique of Autologous Fat Grafting
• Technique of ASC Therapy
• Clinical Application
• Complications and Carcinogenicity of Fat Grafts and ASCs
• Conclusion
• Conflict of Interest
• References

The following sections are included:

• Translational Regenerative Approaches for Bone Reconstruction
• Acknowledgments
• References

Stroke is the third cause of mortality worldwide and the leading cause of long-term disability in adults. However, there are no neuroprotective or neurorestorative therapies approved for ischemic stroke. Based on animal stroke models, cell therapy is a potentially new treatment for regaining neurological functions after stroke. Autologous bone marrow transplantation has demonstrated efficacy in acute stroke models through different mechanisms, such as attenuation of neuronal death, modulation of inflammatory response and stimulation of neuroplasticity and neoangiogenesis, mainly due to secretion of growth factors and cytokines.

There is a scarcity of experience with bone marrow transplantation in stroke patients. We have performed a pilot phase I/II controlled clinical trial to evaluate the safety and feasibility of intra-arterial bone marrow mononuclear cell (BM-MNC) transplantation. Twenty middle cerebral artery (MCA) stroke patients were included, and the outcomes were assessed blinded to the group assignment. Intra-arterial BM-MNCs were injected between 5 and 9 days after stroke and follow-up was done for up to 6 months. The safety and efficacy endpoints were evaluated and also biological effects of cell therapy in serum changes of growth factors and cytokines were also assessed.

In this trial, a total of 1.58 = 10⁸ CM-MNCs were injected into the ipsilateral MCA cases. There were no serious adverse events related to BM-MNC transplantation and there was also no tumour formation during follow-up. Although no significant differences in neurological outcomes were found between both groups, there was a trend to better the functional outcomes with a higher number of CD34+ cells injected. We have also observed some biological effects after transplantation. After BM-MNC injec tion, a positive correlation between the number of BM-MNCs injected and serum levels at 90 days of GM-CSF and PDGF-BB were found and higher levels of nerve growth factor were detec ted as well, 8 days after transplantation.

Based on recent reports in literature and our experience, bone marrow mononuclear cell transplantation is feasible and safe in the acute-subacute phase of ischemic stroke. Changes in serum levels of growth factors detected after injection of BM-MNC are probably due to the secretory function of these cells in the ischemic environment. New clinical trials are ongoing to further assess dose and timing of this therapy and to elucidate the efficacy BM-MNC transplantation.

Subcutaneous fat is emerging as an interesting tissue source for obtaining adipose-derived stromal cells (ASCs) for cellbased therapies in regenerative medicine. The highly heterogeneous, freshly processed stromal vascular fraction (SVF) cells or the expanded adipose-tissue derived mesenchymal stromal cells (MSCs), both are characterised with respect to their regenerative properties. Based on in vitro and preclinical data a number of clinical trials have been initiated to assess their potential clinical benefits. Since basic research is far from the clinical applications, a number of issues emerge and become challenging, when translation of research findings in clinical studies begins. The more progress is achieved with the “bench-to-bedside” approach the more regulatary issues come into place, like: formalities, obligations, regulations, laws and provisions. As there is only limited clinical data available on safety and efficacy, novel cell-based products are highly regulated to assure patient safety and a favorable riskbenefit assessment. To comply with the innovations in regenerative medicine the European Union has classified these novel cell-based drugs as “advanced therapy medicinal products (ATMP).” ATMPs include products derived by gene therapy, somatic cell-based therapy as well as biotechnological therapy, such as tissue engineering. ASCs are considered as ATMPs. In contrast to conventional drugs, ASCs comprise a number of complex biological functions, such as being differentiable, anti-apoptotic, anti-fibrotic, immune regulatory, trophic or pro-regenerative. Nevertheless the regulatory context of ATMPs from preclinical to clinical assessment, to marketing authorisation reclines the authorisation process of classical drugs. This regulatory context also covers the whole manufacturing process from procurement of the tissue, transportation into the manufacturing center, manufacturing, storage, quality control, transport and application to the patient. This cell processing is subsumed under the terms “Good laboratory practice (GLP)” or even “Good manufacturing practice (GMP)” to assure safe and high-quality cell production. Points to consider in the GMP-compliant manufacturing of ASCs will be reviewed in the following.

The following sections are included:

• Background
• Challenges
• Clinical Trials
• Conclusion
• References

The following sections are included:

• Introduction
• Embryonic Cartilage Development and Importance for the Adult Joint Function
• Transfer of the Embryonic Knowledge to Practical Cartilage Repair
• Mesenchymal Stem Cells
• Chondrocytes for Cartilage Repair
• Gene Therapy and Growth Factors
• Scaffolds
• The in vivo Trials with Cultured Chondrocytes
• The clinical Cartilage Repair and Engineering
• Conclusion
• References

Bone tissue normally has the ability of healing. However, in some cases the healing ability is impaired. Delayed healing occurs when the bone does not unify within nine months. If after nine months the bone is still not unified, the term nonunion is used. Regeneration in such cases can be achieved by different methods, depending on the patient's condition. The diamond concept can be applied using cells, biomaterials, growth factors, and mechanical stimulation. Either all factors or just one of the four can be used. Biomaterials can be autograft, allograft or synthetic bone graft substitutes. These can be combined with growth factors for inducing bone formation. Moreover, growth factors for inducing vasculogenesis can also be applied. To apply an array of different growth factors, platelet rich plasma (PRP) can be used. Finally, the cells that are applied should be mesenchymal stem cells. They have the ability to proliferate and differentiate. These mesenchymal stem cells can be derived from bone marrow or adipose tissue. Nowadays, several machines exist for automated isolation of these mesenchymal stem cells. This tissue regeneration concept of applying a biomaterial together with cells and growth factors can lead to an increased success rate of healing of non-union fractures. We have successfully applied these techniques in docking site non-unions and in large defect non-unions of the tibia. Importantly, regenerative medicine uses techniques for personalized medicine.

The following sections are included:

• Introduction
• Models of Bone Tissue Engineering
• The Relevance of Platelet Rich Plasma ( PRP) in Bone-TE
• Bone Tissue Engineering Using BMPs
• Negative Aspects of BMPs
• Carrier Materials and Scaffolds instead of ACS
• Clinical Relevance of DBM
• Combination of DBM and BMPs
• Different Indications presented in Case Studies
• Vertical Bone Regeneration in Periodontal Treatment
• Vertical Bone Regeneration towards Artificial Surfaces (Implants)
• Conclusion
• References

The development of substitutes for the human respiratory system represents a niche application in the rapidly advancing scientific field of Regenerative Medicine covering less than 4% of the published literature. To facilitate a synopsis of the different completed or ongoing research activities applying cell therapies, guided tissue regeneration, or tissue engineering techniques, this book-chapter will summarize the various approaches as bioengineering. We will focus on the biomedical approaches to replace the major airways and the lung and forgo describing the current and potential future transplantation approaches to treat minor airway disease in the large number of patients suffering from cystic fibrosis, COPD, ARDS, pulmonary fibrosis or pulmonary hypertension.

The following section is included:

• Index