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Advanced Drug Delivery Reviews (v.62, #7-8)

Editorial Board (pp. ii).

Therapeutic cell delivery for in situ regenerative medicine by Dong-an Wang Theme Editor; Ram I. Mahato Theme Editor (pp. 669-670).

Carbohydrate engineered cells for regenerative medicine by Jian Du; Kevin J. Yarema (pp. 671-682).

Carbohydrates are integral components of the stem cell niche on several levels; proteoglycans are a major constituent of the extracellular matrix (ECM) surrounding a cell, glycosoaminoglycans (GAGs) help link cells to the ECM and the neighboring cells, and small but informationally-rich oligosaccharides provide a “sugar code” that identifies each cell and provides it with unique functions. This article samples roles that glycans play in development and then describes how metabolic glycoengineering — a technique where monosaccharide analogs are introduced into the metabolic pathways of a cell and are biosynthetically incorporated into the glycocalyx — is overcoming many of the long-standing barriers to manipulating carbohydrates in living cells and tissues and is becoming an intriguing new tool for tissue engineering and regenerative medicine.

Keywords: Metabolic glycoengineering; Glycan and oligosaccharide engineering; Sialic acid; Tissue engineering; ManNAc analogs; Glucosamine; Hexosamine-based drugs

Genetically modified cells in regenerative medicine and tissue engineering by Dima Sheyn; Olga Mizrahi; Shimon Benjamin; Zulma Gazit; Gadi Pelled; Dan Gazit (pp. 683-698).

Regenerative medicine appears to take as its patron, the Titan Prometheus, whose liver was able to regenerate daily, as the field attempts to restore lost, damaged, or aging cells and tissues. The tremendous technological progress achieved during the last decade in gene transfer methods and imaging techniques, as well as recent increases in our knowledge of cell biology, have opened new horizons in the field of regenerative medicine. Genetically engineered cells are a tool for tissue engineering and regenerative medicine, albeit a tool whose development is fraught with difficulties. Gene-and-cell therapy offers solutions to severe problems faced by modern medicine, but several impediments obstruct the path of such treatments as they move from the laboratory toward the clinical setting. In this review we provide an overview of recent advances in the gene-and-cell therapy approach and discuss the main hurdles and bottlenecks of this approach on its path to clinical trials and prospective clinical practice.

Keywords: Gene-and-cell therapy; Genetic engineering; Regenerative medicine; Tissue-specific genes; Tissue engineering; Stem cells

Therapeutic cell delivery and fate control in hydrogels and hydrogel hybrids by Chunming Wang; Rohan R. Varshney; Dong-An Wang (pp. 699-710).

Hydrogels are synthetic or natural polymer networks that closely mimic native extracellular matrices. As hydrogel-based vehicles are being increasingly employed in therapeutic cell delivery, two inherent traits of most common hydrogels, namely low cell affinity and high cell constraint, have significantly drawn the attention of biomedical community. These two properties lead to the unfavourable settlement of anchorage-dependent cells (ADCs) and unsatisfactory cell delivery or tissue formation in hydrogel matrices. Tissue engineers have correspondingly made many efforts involving chemical modification or physical hybridisation to facilitate ADC settlement and promote tissue formation. On the other hand, these two ‘bio-inert’ characteristics have particularly favoured oncological cell therapists, who expect to utilize hydrogels to provide sufficiently high confinement of the delivered cells for anti-cancer purposes. In general, control of cell fate and behaviours in these three-dimensional (3D) microenvironments has become the central aim for hydrogel-mediated cell delivery, towards which various models based on hydrogels and their hybrids have emerged. In this paper, we will first review the development of strategies aiming to overcome the aforementioned two ‘shortcomings’ by (i) establishing ADC survival and (ii) creating space for tissue formation respectively, and then introduce how people take advantage of these ‘disadvantages’ of hydrogel encapsulation for (iii) an enhanced confinement of cell motion.

Keywords: Hydrogels; Cell delivery; In situ; therapy; Tissue engineering; Regenerative medicine; Anti-cancer

Microcapsules and microcarriers for in situ cell delivery by Rosa M Hernández; Gorka Orive; Ainhoa Murua; José Luis Pedraz (pp. 711-730).

In recent years, the use of transplanted living cells pumping out active factors directly at the site has proven to be an emergent technology. However a recurring impediment to rapid development in the field is the immune rejection of transplanted allo- or xenogeneic cells. Immunosuppression is used clinically to prevent rejection of organ and cell transplants in humans, but prolonged usage can make the recipient vulnerable to infections, and increase the likelihood of tumorigenesis of the transplanted cells. Cell microencapsulation is a promising tool to overcome these drawbacks. It consists of surrounding cells with a semipermeable polymeric membrane. The latter permits the entry of nutrients and the exit of therapeutic protein products, obtaining in this way a sustained delivery of the desirable molecule. The membrane isolates the enclosed cells from the host immune system, preventing the recognition of the immobilization cells as foreign. This review paper intends to overview the current situation in the cell encapsulation field and discusses the main events that have occurred along the way. The technical advances together with the ever increasing knowledge and experience in the field will undoubtedly lead to the realization of the full potential of cell encapsulation in the future.

Keywords: Cell encapsulation; Alginate–PLL–alginate; Cell therapy; Drug delivery; Engineered cells; Stem cells

Nanomaterials for in situ cell delivery and tissue regeneration by Andrew C.A. Wan; Jackie Y. Ying (pp. 731-740).

Nanomaterials can be defined as materials that possess clearly defined features of less than 100nm, and whose nanostructured features confer characteristics crucial to the material's bulk property. The nanostructured features can be an intermediate or final state of the material in its synthesis process. The field of nanomaterials as applied to in situ cell delivery and tissue engineering is rapidly expanding. Nanomaterials that include peptide amphiphiles, self-assembling peptides, electrospun scaffolds, layer-by-layer complexes, nanotubes and nanocomposites have been applied to cell culture, encapsulation and delivery with promising results. As compared to scaffold-free cell delivery, nanomaterials are advantageous in terms of providing a means to control the biochemical and mechanical microenvironment of the cells. Nanomaterials are amenable to a bottom-up approach in functionalization and mechanical tuning, as illustrated in the examples presented in this review. Furthermore, nanomaterials such as DNA polyplexes and carbon nanotubes can also be incorporated into the cell delivery vehicle to improve the regenerative outcome. Lastly, while nanomaterials harbor much potential for cell delivery and tissue regeneration, further characterization is required in terms of clinical safety before these materials can be employed towards therapeutic applications.

Keywords: Definition; Nanomaterials; Cell delivery; Microenvironment; Tissue regeneration; Tissue engineering

Potential of endogenous regenerative technology for in situ regenerative medicine by Eduardo Anitua; Sanchez Mikel Sánchez; Gorka Orive (pp. 741-752).

Endogenous regenerative technology (Endoret) involves the use of patient's own biologically active proteins, growth factors and biomaterial scaffolds for therapeutic purposes. This technology provides a new approach for the stimulation and acceleration of tissue healing and bone regeneration. The versatility and biocompatibility of using patient-derived fibrin scaffold as an autologous, biocompatible and biodegradable drug delivery system open the door to a personalized medicine that is currently being used in numerous medical and scientific fields including dentistry, oral implantology, orthopaedics, ulcer treatment, sports medicine and tissue engineering among others. This review discusses the state of the art and new directions in the use of endogenous technology in the repair and regeneration of injured tissues by means of a controlled and local protein and growth factor delivery. The next generations of engineering strategies together with some of the most interesting therapeutic applications are discussed together with the future challenges in the field.

Keywords: Growth factors; Endogenous regenerative medicine; Platelets; Fibrin; Scaffolds; Biomaterials

Scaffold-free cell delivery for use in regenerative medicine by Jens M. Kelm; Martin Fussenegger (pp. 753-764).

The development of cell-based therapies for diseased tissues is one of the most promising research directions in regenerative medicine. Cell-delivery methods are an essential part of cell therapy concepts. Therapies with the potential to become clinical routine will only be possible if these methods ensure efficient engraftment and therapeutically-relevant number of cells survive. Here we provide an overview of three different scaffold-free cell-delivery concepts: (i) single cell delivery, (ii) cell sheet engineering and (iii) microtissue technology.

Keywords: Stem cells; Cell sheets; Microtissues; Tissue engineering

Cell delivery therapeutics for musculoskeletal regeneration by Noth Ulrich Nöth; Lars Rackwitz; Andre F. Steinert; Rocky S. Tuan (pp. 765-783).

The last decade has witnessed the development of cell-based therapy as a major biomedical research area, including the treatment of musculoskeletal diseases. Both differentiated and undifferentiated stem cells have been used as starting cell sources. In particular, the use of multipotent adult mesenchymal stem cells holds great promise for future therapeutic strategies. In addition to the cell type used, the cell delivery system is also of critical importance in cell-based therapy. Cell delivery may be achieved by direct cell injection or by grafting engineered constructs derived by cell seeding into natural or synthetic biomaterial scaffolds. While direct injection is the most direct and convenient means of cell delivery, the latter approach is capable of producing three-dimensional engineered tissues with mechanical properties compatible with those of various musculoskeletal tissues. This review will focus on the functional approach of using biomaterial scaffold materials as cell carriers for musculoskeletal applications, as well as the use of cell-based gene therapy for tissue engineering and regeneration.

Keywords: Cell-based therapy; Cell delivery; Mesenchymal stem cells; Embryonic stem cells; Natural and synthetic biomaterials; Gene delivery; Musculoskeletal regeneration

Cellular cardiomyoplasty and cardiac tissue engineering for myocardial therapy by Feng Wang; Jianjun Guan (pp. 784-797).

Heart diseases, including myocardial infarction (MI) and congestive heart failure (CHF), have high mortality rates. Both MI and CHF are characterized by cardiac muscle damage caused by massive cardiomyocyte death and reduced cardiac function. Cellular therapy aimed at using cells to improve cardiac function and/or regenerate new myocardium, has been extensively investigated for cardiac repair. Two strategies have been currently taken for cellular transplantation, including in situ cellular cardiomyoplasty and cardiac tissue engineering. The in situ cellular cardiomyoplasty strategy delivers cells directly into the infarcted myocardium. A variety of cell types has been shown to be beneficial in cardiac repair. However, this strategy is limited in terms of cell retention, survival of the engrafted cells, cell differentiation, and integration of transplanted cells with host tissue. Cardiac tissue engineering is an alternate strategy to in situ cellular cardiomyoplasty, which is designed to repair infarcted myocardium using cells, biomaterials and regulative factors (for example growth factors). There are currently various approaches for cardiac tissue engineering, such as, in situ delivering cells with injectable biomaterials into the infarcted myocardium, in vitro engineering of contractile tissue constructs followed by in vivo implantation, in vitro engineering of stem cell loaded tissue constructs for in vivo myocardium regeneration, and cell sheet tissue engineering. This review provides a comprehensive progress of in situ cellular cardiomyoplasty and cardiac tissue engineering for cardiac repair.

Keywords: Myocardial infarction; Congestive heart failure; Cell therapy; Tissue engineering; Biomaterials; Growth factor delivery

Cell-delivery therapeutics for adipose tissue regeneration by Petra Bauer-Kreisel; Achim Goepferich; Torsten Blunk (pp. 798-813).

In reconstructive surgery, there is a tremendous clinical need for adequate implants to repair soft tissue defects resulting from traumatic injury, tumor resection, or congenital anomalies. Adipose tissue engineering holds the promise to provide answers to this still increasing demand.The current approaches to adipose tissue engineering are comprehensively reviewed detailing the different cell carriers under investigation. A special focus is put on the applied cells. The delivered mesenchymal stem cells act in a dual role as building block of the new tissue and modulators of the host response. The conditioning of the cells in vitro prior to implantation decisively influences the tissue development and long-term survival in vivo. The special role of vascularization in adipose engineering is discussed. In all parts, key messages are defined providing the base for future advances in the generation of fat substitutes.

Keywords: Adipose tissue engineering; Adipogenesis; Adipose-derived stem cells; Mesenchymal stem cells; Differentiation; Microenvironment; Biomaterials; Vascularization

Cell-delivery therapeutics for liver regeneration by Wenxia Zhang; Lisa Tucker-Kellogg; B.C. Narmada; Lakshmi Venkatraman; Shi Chang; Yin Lu; Nancy Tan; Jacob K. White; Ruirui Jia; Sourav Saha Bhowmick; Shali Shen; C. Forbes Dewey Jr.; Hanry Yu (pp. 814-826).

For acute, chronic, or hereditary diseases of the liver, cell transplantation therapies can stimulate liver regeneration or serve as a bridge until liver transplantation can be performed. Recently, fetal hepatocytes, stem cells, liver progenitor cells, or other primitive and proliferative cell types have been employed for cell transplantation therapies, in an effort to improve the survival, proliferation, and engraftment of the transplanted cells. Reviewing earlier studies, which achieved success by transplanting mature hepatocytes, we propose that there is a switch-like regulation of liver regeneration that changes state according to a stimulus threshold of extracellular influences such as cytokines, matrices and neighboring cells. Important determinants of a successful clinical outcome include sufficient quantities and functional levels of the transplanted cells (even for short periods to alter the environment), rather than just engraftment levels or survival durations of the exogenously transplanted cells. The relative importance of these determining factors will impact future choices of cell sources, delivery vehicles, and sites of cell transplantation to stimulate liver regeneration for patients with severe liver diseases.

Keywords: Cell transplantation; Liver regeneration; Hepatocytes; Stem cells; Xenogenic cells; Delivery vehicles; Scaffolds; Encapsulation; Systems Biology

Bioartificial pancreas by Yuji Teramura; Hiroo Iwata (pp. 827-840).

Type 1 diabetes has been successfully treated by transplanting islets of Langerhans (islets), endocrine tissue releasing insulin. Serious issues, however, still remain. The administration of immunosuppressive drugs is required to prolong graft functioning; however, side effects of their long-term use on recipients are not fully understood, and cell transplantation therapy without the use of immunosuppressive drugs is desired. To resolve these issues, the encapsulation of isles with a semi-permeable membrane, or bioartificial pancreas, has been attempted. Many groups have reported that it functions very well in small animal models. Few of the bioartificial pancreases, however, were applied to human patients and their clinical outcome was not clear. In this review, we address obstacles and overview new techniques to overcome these issues, such as conformal coating and islet enclosure with cells.

Keywords: Cell transplantation; Islet; Bioartficial pancreas; Encapsulation; Surface modification; Islet transplantation; Conformal coating

Cell and drug delivery therapeutics for controlled renal parenchyma regeneration by Will W. Minuth; Lucia Denk; Anne Glashauser (pp. 841-854).

In regenerative medicine much attention is given to stem/progenitor cells for a future therapy of acute and chronic renal failure. However, up to date sound cell biological knowledge about nephron renewal in kidney is lacking. For that reason molecular mechanisms are under intense investigation leading from stem/progenitor cells to regenerated tubules. In this coherence new biomaterials and drug delivery systems have to be elaborated showing an intense stimulation on the renewal of parenchyma.To analyze tubule regeneration a powerful culture system is of fundamental importance. An advanced technique stimulates renal stem/progenitor cells to develop numerous tubules between layers of a polyester fleece. Use of chemically defined Iscove's Modified Dulbecco's Medium (IMDM) containing aldosterone (1×10−⁷M) results in spatial development of renal tubules within 13days of perfusion culture.Immunohistochemistry exhibits that numerous features of a polarized epithelium are expressed in generated tubules. Transmission electron microscopy (TEM) illuminates that generated tubules contain a polarized epithelium with a tight junctional complex and an intact basal lamina at the basal aspect.Development of tubules depends on applied aldosterone concentration and cannot be mimicked by precursors of its synthesis pathway or by other steroid hormones. Antagonists such as spironolactone or canrenoate prevent the development of tubules. This result illuminates that the tubulogenic development is mediated via the mineralocorticoid receptor (MR). Application of geldanamycin, radicicol, quercetin or KNK 437 in combination with aldosterone blocks development of tubules by disturbing the contact between MR and heat shock proteins 90 and 70.In conclusion, for the first time generation of renal tubules can be simulated under controlled in-vitro conditions. Using this model the effect of numerous innovative biomaterials and drug delivery system can be critically analyzed.

Keywords: Kidney; Stem/progenitor cells; Tubules; Aldosterone; Perfusion culture; Artificial interstitium; Biomaterial; Drug delivery

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Advanced Drug Delivery Reviews (v.62, #7-8)