Table of Contents

Volume 6, Issue 3

  July/August/September 2010

  Pages 139 - 194

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EDITORIAL

Open Access Article

Engineering towards functional tissues and organs

Suwan N. Jayasinghe
Pages 139 - 140
http://dx.doi.org/10.4161/org.6.3.12901
Abstract | PDF

Engineering towards fully functional tissues and organs fall under the widespread banner of tissue engineering and regenerative biology/medicine (which includes therapeutics). This endeavor is said to evolve from the Greek mythical story¹ where Prometheus is punished by Zeus who assigned a long winged eagle to feed on Prometheus’s liver, for stealing fire from the Gods. It is said that Prometheus’s liver grew as much it was eaten. Thus, conceptualizing tissue engineering and regenerative medicine. This in its very early stages was investigated by Alexis Carrel and Charles Lindbergh at the Rockefeller Institute for Medical Research² and was subsequently clinically implemented in 1954 in renal transplantation medicine in the United States by Joseph Murray and colleagues.3 Both Carrel and Murray were awarded Nobel Prizes for their findings and contributions.⁴ Although these are hallmarks for tissue engineering and regenerative medicine, there are many obstacles and to date we are still grappling with some of these hurdles whist others have to a great extent been understood, and could be argued as being to some degree resolved. Some obstacles we face today range from (1) the ability to grow specialized and unspecialized cells outside the human body in practical quantities while retaining their native functionality, (2) biomaterials (advancing the development of synthetic materials for enhanced bioactivity), (3) advanced approaches for forming three-dimensional fully functional tissues and or organs to (4) controlled vascularization, which are a few examples amongst many.




REVIEWS: ENGINEERING TOWARD FUNCTIONAL TISSUES AND ORGANS

Open Access Article

Amphibians as research models for regenerative medicine

Fengyu Song, Bingbing Li and David L. Stocum
Pages 141 - 150
http://dx.doi.org/10.4161/org.6.3.12039
Abstract | PDF

The ability to regenerate bone across a critical size defect would be a marked clinical advance over current methods for dealing with such structural gaps. Here, we briefly review the development of limb bones and the mandible, the regeneration of urodele limbs after amputation, and present evidence that urodele and anuran amphibians represent a valuable research model for the study of segment defect regeneration in both limb bones and mandible.

Open Access Article

Strategies for organ level tissue engineering

Kristine C. Rustad, Michael Sorkin, Benjamin Levi, Michael T. Longaker and Geoffrey C. Gurtner
Pages 151 - 157
http://dx.doi.org/10.4161/org.6.3.12139
Abstract | PDF

The field of tissue engineering has made considerable strides since it was first described in the late 1980s. The advent and subsequent boom in stem cell biology, emergence of novel technologies for biomaterial development, and further understanding of developmental biology have contributed to this accelerated progress. However, continued efforts to translate tissue engineering strategies into clinical therapies have been hampered by the problems associated with scaling up laboratory methods to produce large, complex tissues. The significant challenges faced by tissue engineers include the production of an intact vasculature within a tissue-engineered construct and recapitulation of the size and complexity of a whole organ. Here we review the basic components necessary for bioengineering organs – biomaterials, cells and bioactive molecules–and discuss various approaches for augmenting these principles to achieve organ level tissue engineering. Ultimately, the successful translation of tissue-engineered constructs into everyday clinical practice will depend upon the ability of the tissue engineer to “scale up” every aspect of the research and development process.

Open Access Article

Vascular organogenesis: Dream or reality?

Beat H. Walpoth
Pages 158 - 160
http://dx.doi.org/10.4161/org.6.3.12334
PDF

Open Access Article

Development, characterization and clinical use of a biodegradable composite scaffold for bone engineering in oro-maxillo-facial surgery

John E. Davies, Rano Matta, Vanessa C. Mendes and Paulo S. Perri de Carvalho
Pages 161 - 166
http://dx.doi.org/10.4161/org.6.3.12392
Abstract | PDF

We have developed a biodegradable composite scaffold for bone tissue engineering applications with a pore size and interconnecting macroporosity similar to those of human trabecular bone. The scaffold is fabricated by a process of particle leaching and phase inversion from poly(lactide-co-glycolide) (PLGA) and two calcium phosphate (CaP) phases both of which are resorbable by osteoclasts; the first a particulate within the polymer structure and the second a thin ubiquitous coating. The 3-5 µm thick osteoconductive surface CaP abrogates the putative foreign body giant cell response to the underlying polymer, while the internal CaP phase provides dimensional stability in an otherwise highly compliant structure. The scaffold may be used as a biomaterial alone, as a carrier for cells, or a three-phase drug delivery device. Due to the highly interconnected macroporosity ranging from 81% to 91%, with macropores of 0.8~1.8 mm, and an ability to wick up blood, the scaffold acts as both a clot-retention device and an osteoconductive support for host bone growth. As a cell delivery vehicle, the scaffold can be first seeded with human mesenchymal cells which can then contribute to bone formation in orthotopic implantation sites, as we show in immune-compromised animal hosts. We have also employed this scaffold in both lithomorph and particulate forms in human patients to maintain alveolar bone height following tooth extraction, and augment alveolar bone height through standard sinus lift approaches. We provide a clinical case report of both of these applications; and we show that the scaffold served to regenerate sufficient bone tissue in the wound site to provide a sound foundation for dental implant placement. At the time of writing, such implants have been in occlusal function for periods of up to 3 years in sites regenerated through the use of the scaffold.

Open Access Article

Advances in musculoskeletal tissue engineering: Moving towards therapy

Carlo Alberto Rossi, Michela Pozzobon and Paolo De Coppi
Pages 167 - 172
http://dx.doi.org/10.4161/org.6.3.12419
Abstract | PDF

Skeletal muscle can self-repair, but is unable to restore significant tissue loss, as consequence of trauma, congenital defects, tumor ablation, or denervation. Intramuscular injection of autologous or allogenic derived myogenic cells (namely satellite cells and myoblasts) did not lead to efficient regeneration because of poor cell retention and survival, as well as immunorejection. In the last decade, tissue engineering looked at overcoming these problems by investigating alternative treatment options, i.e. the suspension of myogenic precursors in temporary matrix, formed by biodegradable and biocompatible materials. This approach allows to engineer custom architectured preconditioned implants, and locally deliver paracrine factors. This article reviews current and potential strategies for the repair of damaged muscle and suggests some innovative approaches for the translation to the clinical setting.




RESEARCH PAPERS: ENGINEERING TOWARD FUNCTIONAL TISSUES AND ORGANS

Open Access Article

Injectable in situ forming biodegradable chitosan-hyaluronic acid based hydrogels for adipose tissue regeneration

Huaping Tan, J. Peter Rubin and Kacey G. Marra
Pages 173 - 180
http://dx.doi.org/10.4161/org.6.3.12037
Abstract | PDF

An injectable, biodegradable and glucose-responsive hydrogel derived from natural polysaccharide derivatives was synthesized to deliver adipogenic factor of insulin in vitro for adipose tissue engineering. The biodegradable hydrogel based N-succinyl-chitosan (SCS) and aldehyde hyaluronic acid (AHA) with covalently conjugated glucose oxidase and catalase. The gelation is attributed to the Schiff-base reaction between amino and aldehyde groups of SCS and AHA, respectively. The morphologies and compressive modulus of the freeze-dried hydrogels demonstrated that the incorporated insulin and enzymes results in the formation of a tighter network structure in composite hydrogels. The immobilized enzymes triggered conversion of glucose reduces the pH value of the microenvironment, and results in hydrolysis and increasing swelling of the network basing on Schiff-base cross-linking. The pH inside the hydrogel, kept in PBS solution at pH 7.4 and 37oC, linearly dropped from 7.40 to 7.17 during 4 h of initial period, then slowly increased to 7.36 after 24 h. Correspondingly, the swelling ratio increased from 20.8 to 28.6 at 37oC in PBS with 500 mg/dL glucose. In PBS buffer with 500mg/dL glucose, about 10.8 % of insulin was seen to be released from the hydrogel after 8 h of incubation. The results demonstrated that the adipogenic factor of insulin would be released from this biodegradable hydrogel device into the local microenvironment in a controlled fashion by the swelling of hydrogel network. These preliminary studies indicate that the biodegradable and glucose-responsive hydrogel may have potential uses in adipose tissue engineering applications.

Open Access Article

Interactions between human osteoblasts and prostate cancer cells in a novel 3D in vitro model

Shirly Sieh, Amy A. Lubik, Judith A. Clements, Colleen C. Nelson and Dietmar W. Hutmacher
Pages 181 - 188
http://dx.doi.org/10.4161/org.6.3.12041
Abstract | PDF

Cell-cell and cell-matrix interactions play a major role in tumor morphogenesis and cancer metastasis. Therefore, it is crucial to create a model with a biomimetic microenvironment that allows such interactions to fully represent the pathophysiology of a disease for an in vitro study. This is achievable by using three-dimensional (3D) models instead of conventional two-dimensional (2D) cultures with the aid of tissue engineering technology. We are now able to better address the complex intercellular interactions underlying prostate cancer (CaP) bone metastasis through such models. In this study, we assessed the interaction of CaP cells and human osteoblasts (hOBs) within a tissue engineered bone (TEB) construct. Consistent with other in vivo studies, our findings show that intercellular and CaP cell-bone matrix interactions lead to elevated levels of matrix metalloproteinases, steroidogenic enzymes and the CaP biomarker, prostate specific antigen (PSA); all associated with CaP metastasis. Hence, it highlights the physiological relevance of this model. We believe that this model will provide new insights for understanding of the previously poorly understood molecular mechanisms of bone metastasis, which will foster further translational studies, and ultimately offer a potential tool for drug screening.




RESEARCH PAPER

Open Access Article

The relationship between nephron number, kidney size and body weight in two inbred mouse strains

Inga J. Murawski, Rita W. Maina and Indra R. Gupta
Pages 189 - 194
http://dx.doi.org/10.4161/org.6.3.12125
Abstract | PDF

While some reports in humans have shown that nephron number is positively correlated with height, body weight or kidney weight, other studies have not reproduced these findings. To understand the impact of genetic and environmental variation on these relationships, we examined whether nephron number correlates with body weight, kidney planar surface area, or kidney weight in two inbred mouse strains with contrasting kidney sizes but no overt renal pathology: C3H/HeJ and C57BL/6J. C3H/HeJ mice had smaller kidneys at birth and larger kidneys by adulthood, however there was no significant difference in nephron number between the two strains. We did observe a correlation between kidney size and body weight at birth and at adulthood for both strains. However, there was no relationship between nephron number and body weight or between nephron number and kidney size. From other studies, it appears that a greater than 2-fold variation is required in each of these parameters in order to demonstrate these relationships, suggesting they are highly dependent on scale. Our results are therefore not surprising since there was a less than 2-fold variation in each of the parameters examined. In summary, the relationship between nephron number and body or kidney size is most likely to be demonstrated when there is greater phenotypic variation either from genetic and/or environmental factors.