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PubMed2005

Rapid and complete cellularization of hydroxyapatite for bone tissue engineering.

Using a tissue construct generated by cells in a scaffold in reconstructive surgery, as a substitute for autografts, is still challenging. Routine methods of incorporating cells into scaffolds are either passive, i.e. by gravity, or forced, as in a bioreactor. Extensive use of these methods is obstructed by tissue formation around the scaffold, hindrance in cell penetration and time required for cell coverage within the scaffold. In this study, human osteoblast cells as cell sheet structures were seeded to porous and dense hydroxyapatite with the hypothesis that preservation of native extracellular structures and cell-cell contacts would facilitate the cellularization process. Cellularization was assessed by fluorescence, confocal and scanning electron microscopy at intervals of 1 h, 2 days and 7 days. Cell patches with intact cell-cell and cell-extra cellular matrix contact attached and adhered on a scaffold within 1 h. The patches formed a monolayer within 2 days and complete cellularization of the scaffold was attained in 7 days. Cell viability, proliferation and function were assessed to understand the application of cell patch transfer to bone substitute. This novel approach for application in bone tissue engineering was successful in uniform distribution of intact osteoblast cell sheet structures on to bone substitute materials for rapid and complete cellularization without altering material characteristics.

Bone Substitutes↗
PubMed2003

[Regulatory role of mechanical stress response in cellular function: development of new drugs and tissue engineering].

The investigation of mechanotransduction in the cardiovascular system is essentially important for elucidating the cellular and molecular mechanisms involved in not only the maintenance of hemodynamic homeostasis but also etiology of cardiovascular diseases including arteriosclerosis. The present review summarizes the latest research performed by six academic groups, and presented at the 75th Annual Meeting of the Japanese Pharmacological Society. Technology of cellular biomechanics is also required for research and clinical application of a vascular hybrid tissue responding to pulsatile stress. 1) Vascular tissue engineering: Design of pulsatile stress-responsive scaffold and in vivo vascular wall reconstruction (T. Matsuda); 2) Cellular mechanisms of mechanosensitive calcium transients in vascular endothelium (M. Oike et al.); 3) Cross-talk of stimulation with fluid flow and lysophosphatidic acid in vascular endothelial cells (K. Momose et al.); 4) Mechanotransduction of vascular smooth muscles: Rate-dependent stretch-induced protein phosphorylations and contractile activation (K. Obara et al.); 5) Lipid mediators in vascular myogenic tone (I. Laher et al.); and 6) Caldiomyocyte regulates its mechanical output in response to mechanical load (S. Sugiura et al.).

Animals↗
PubMed2003

Repair of calvarial defects with customised tissue-engineered bone grafts II. Evaluation of cellular efficiency and efficacy in vivo.

We have demonstrated in Part I of this study [see Schantz, J.-T., et al., Tissue Eng. 2003;9(Suppl. 1): S-113-S-126; this issue] that bone marrow-derived progenitor cells and calvarial osteoblasts could be successfully directed into the osteogenic lineage and cultured in three-dimensional (3-D) polycaprolactone (PCL) scaffolds. The objective of the second part of the study was to evaluate and to compare tissue engineered cell-polymer constructs using calvarial osteoblasts (group I) and mesenchymal progenitor cells (MPCs; group II) for the reconstruction of critical-size and three-dimensionally complex cranial defects. In 30 New Zealand White rabbits, bilateral parietal critical-size defects were created. On the basis of computed tomography scans, customized PCL scaffolds with precisely controlled microarchitecture were fabricated, using a rapid prototyping technology. Bone marrow-derived progenitor cells and osteoblasts were isolated and expanded in culture. Osteoblasts (group I) and mesenchymal progenitor cells (group II) were seeded in combination with a fibrin glue suspension into 40 PCL scaffolds. After incubating for 3 days in static culture, the PCL scaffold-cell constructs as well as nonseeded PCL scaffolds (control group) were implanted into 15-mm-diameter calvarial defects. Reconstruction of the cranium and bone formation were evaluated after 3 months. In vivo results indicated osseous tissue integration within the implant and functionally stable restoration of the calvarium. Islands of early bone formation could be observed in X-ray radiographs and in histological sections. Implants showed a high cell:ECM ratio and a dense vascular network. Mechanical testing of the reconstructed area revealed partial integration with the surrounding corticocancellous calvarial bone. The amount (area) of calcification, measured by clinical computed tomography, indicated that cell-seeded constructs measured about 60% more than unrepaired or unseeded scaffolds. Mechanical investigations revealed that stiffness reached 52 +/- 29 and 44 +/- 16 MPa for MPC- and osteoblast-seeded scaffolds, respectively. The yield strength for the push-out tests was 180 +/- 36 N for normal calvarial bone, 90 +/- 1 N for unrepaired site, and 106 +/- 10 N for unseeded constructs, which is about 60% of normal bone strength. MPC- and osteoblast-seeded scaffolds indicated a yield strength of 149 +/- 15 and 164 +/- 42 N, respectively, which is about 85-90% of normal bone. This study demonstrated that customized biodegradable polymeric implants may be used to deliver osteogenic cells and enhance bone formation within critically-sized defects in vivo. The use of rapid prototyping technology to produce scaffolds with controlled external geometry and microarchitecture offers new possibilities in the functional and aesthetic reconstruction of complex craniofacial defects.

Animals↗
PubMedDate not supplied

Characterization of the cellular origin of a tissue-engineered human phalanx model by in situ hybridization.

Tissue-engineered models of human phalanges have previously been fabricated from a combination of bovine periosteum, cartilage, tendon, and biodegradable polyglycolic acid and poly-L-lactic acid scaffolds. Resulting constructs implanted in athymic mice for more than 40 weeks developed new bone, cartilage, and tendon and became vascularized, but cell types comprising the constructs were unidentified. The origin of cells in middle phalanx models implanted for 20 weeks in nude mice has been studied by in situ hybridization analyzing species-specific gene expression. Oligonucleotide probes homologous to species-specific gene sequences of bovine type II and X collagen, aggrecan, bone sialoprotein, biglycan, and osteopontin, and mouse decorin were labeled with (35)S and hybridized to respective serial sections of bovine tissue, mouse tissue, and phalanx constructs. In situ hybridization showed positive message and tissue-specific localization for all bovine-specific probes examined within cartilaginous and midshaft portions of constructs and negative message for the mouse-specific decorin probe. These data show that osteoblasts and chondrocytes comprising constructs are derived exclusively from their original bovine sources over 20 weeks of implantation. Defining the cellular origin of the models lends insight into their biological, chemical, and physical nature and their growth and development. Maintenance of their initial genotype is crucial for future application of the models in augmenting impaired human phalanges and related tissues.

Animals↗
PubMed2026

Recent advances in molecular mechanisms to improve the efficacy of CAR-T cell therapy for viral diseases, cancer, and autoimmune diseases.

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, yet its broader application to solid tumors, chronic viral infections, and autoimmune diseases remains constrained by antigen heterogeneity, immunosuppressive tissue microenvironments, T-cell exhaustion, limited persistence, and treatment-associated toxicities. These challenges have shifted the field from optimizing individual receptor constructs toward engineering CAR-T cells as programmable immune systems capable of adapting to diverse disease contexts. This review synthesizes recent advances in molecular engineering strategies that enhance CAR-T cell function beyond conventional receptor design. We discuss how receptor engineering, genome editing, transcriptional and epigenetic regulation, metabolic reprogramming, synthetic gene circuits, and safety-control platforms collectively reshape CAR-T cell fate, persistence, and therapeutic efficacy. Rather than functioning independently, these engineering strategies are increasingly integrated to generate context-specific cellular therapies capable of adapting to diverse disease environments, including cancer, autoimmune diseases, and chronic viral infections. We also highlight the potential for translation into clinical practice or clinical translation and discuss the major challenges associated with clinical implementation. Next-generation CAR-T therapies will increasingly integrate molecular engineering strategies or will rely on molecular engineering strategies to integrate antigen recognition, cellular fitness, immune regulation, and longevity rather than simply maximizing cytotoxic activity. Recent advances in programmable cellular engineering coupled with rigorous clinical evaluation as well as scalable manufacturing technologies or scalable manufacturing platforms in the treatment of other diseases beyond oncology will facilitate the development of safer, more durable, and broadly applicable cellular therapies.

Humans↗
PubMed2002

Adipose tissue processed for lipoinjection shows increased cellular survival in vitro when tissue engineering principles are applied.

Correcting soft tissue defects by autologous fat grafting is a routine procedure in plastic surgery. Its efficacy and safety has been discussed extensively and several techniques of lipoinjection have been developed. However, one is bound to overcorrect by 30%-70% or need to repeat the procedure because of resorption of the transplant. The reasons are that many of the transplanted cells are already differentiated, and also that there is no nutritional support to the inner cell layers when they are transplanted as fragments. By culturing autologous adipocytes one can ensure that only non-differentiated, but committed, preadipocytes are transplanted and the procedure can be done in a way that ensures optimal nutritional support for the cells. In the present study we have compared our cell culture technique with two common clinical ways of processing liposuction material and found that (pre)adipocytes survive and proliferate significantly better in cell culture.

Abdomen↗
PubMed2000

Engineering a living cell to desired metabolite concentrations and fluxes: pathways with multifunctional enzymes.

With molecular genetics enabling modulation of the concentrations of cellular enzymes, metabolic engineering becomes limited by the question of which modulations of the enzyme concentrations are required to bring about a desired pattern of cellular metabolism. In an earlier paper (Kholodenko et al. (1998). Biotechnol. Bioeng. 59, 239-247) we derived a method to determine the required modulations. This method, however, cannot be immediately applied to cellular pathways with enzymes catalyzing more than one step in metabolism (multifunctional enzymes). In the present paper we show to which extent the presence of multifunctional enzymes limits biotechological ambitions, which one might otherwise pursue in vain. In particular, it is impossible to change the concentration of a single intermediate and leave the rest of metabolism unperturbed if that intermediate interacts directly with a multifunctional enzyme. The analytical machinery of Metabolic Control Analysis is used to relate the desired and ensuing changes in the metabolic pattern. An explicit solution to this problem of engineering metabolism is then given in the form of a single matrix equation.

Animals↗
PubMed2005

Enhanced insulin secretion from engineered 3T3-L1 preadipocytes by induction of cellular differentiation.

We have established insulin-secreting cell line, L1-INS/fur cells, by engineering 3T3-L1 murine preadipocytes with human preproinsulin cDNA. Analysis with HPLC, mass spectrometry and immunological assay identified human insulin in the culture medium. Notably, secretion of insulin from L1-INS/fur cell was increased 8.2 times higher after induction of cellular differentiation. The increment of insulin secretion during differentiation was further enhanced by additive treatment with thiazolidinedione, a promoting agent of adipocyte differentiation. This observation strongly suggests that the enhancement of insulin secretion is tightly associated with cellular differentiation process itself. Expression rate of the insulin transgene was not changed after the additional treatment with thiazolidinedione. On the other hand, furin gene expression by Northern analysis showed an increase, and Western analysis revealed even more reduction in cellular content of proinsulin. These results indicate that mechanism of the observed enhancement in insulin secretion during the differentiation is mainly due to increased capacity of the proinsulin processing by induction of furin. Results of our present study will provide important information on cell-based therapy using undifferentiated progenitors and tissue stem cells.

3T3-L1 Cells↗
PubMed2004

Cellular alignment by grafted adhesion peptide surface density gradients.

The extracellular matrix and extracellular matrix-associated proteins play a major role in growth and differentiation of tissues and organs. To date, few methods have been developed that allow researchers to examine the affect of surface density gradients of adhesion molecules in a controlled manner. Fibroblasts cultured on surfaces with a surface density gradient of RGD peptide aligned parallel to the gradient while fibroblasts on constant density RGD surfaces spread but did not align as has been shown in numerous earlier studies. Not only did fibroblasts align on the gradient surfaces, but they also showed significantly greater elongation than on constant density peptide surfaces or on control surfaces. This type of method is easy to replicate and can be used by laboratories interested in investigating alignment of various cell types without mechanical force or other stimulation, and without cell-cell interaction or for investigation of affects of surface density gradients of molecules on cellular biochemistry and biophysics. This method also has potential applications for developing scaffolds for tissue engineering applications where cellular alignment is necessary.

Animals↗
PubMed1999

A dedication in memoriam of Dr. Richard Skalak.

Richard Skalak (1923-1997) played a leadership role in the formative decades of the discipline of biomedical engineering through his technical contributions in biomechanics, his educational influence on students, and his service to many developing societies and journals. But always, the distinguishing marks of his involvement with any activity or person were his generosity, respect and tolerance for others, integrity, and curiosity. These very qualities are what first brought him as a traditional engineering trained in engineering mechanics into the young field of biomedical engineering in the 1960s, and they are what led him to new approaches to cellular and molecular engineering, tissue engineering, and orthopedic biomechanics. His technical papers and lectures on blood cell mechanics, pulmonary circulation, dental implants, and tissue growth were models of clarity and often pointed the way to new areas of exploration, while his personal writings offer advice on life, academic organizations, and the pursuit of significant work. He would be deeply appreciative that this first volume of the Annual Review of Biomedical Engineering is dedicated to his memory.

Animals↗
PubMed2004

Inverse modeling using multi-block PLS to determine the environmental conditions that provide optimal cellular function.

MOTIVATIONS: Tissue engineering constitutes an important field with its potential of addressing the current shortage in organ availability. To successfully develop tissue-engineered organs, it is crucial to understand how to maintain the cells under conditions that maximize their ability to perform their physiological roles, regardless of the environment, whether the cells are part of an extracorporeal system, such as the bioartificial liver assist device, or an implantable tissue-engineered device. Our goals are to (1) provide insight into how cells will behave when confronted with changes in its environment and (2) determine the optimal environmental factors to achieve a desired level of cellular function. RESULTS: Diverse sets of environmental factors were used to systematically perturb the metabolic behavior associated with pre-conditioning and plasma supplementation. To probe metabolic state of hepatocytes, metabolic flux analysis was used to obtain the metabolic profile. We applied a multi-block partial least square (MPLS) model to relate environmental factors and fluxes to levels of intracellular lipids and urea synthesis. The MPLS model identified: (1) the most influential environmental factors and (2) how the metabolic pathways are altered by these factors. Finally, we inverted the MPLS model to determine the concentrations and types of environmental factors required to obtain the most economical solution for achieving optimal levels of cellular function for practical situations.

Amino Acids↗
PubMed2006

Micropatterning polyvinyl alcohol as a biomimetic material through soft lithography with cell culture.

Integrating inorganic materials with specific biological systems requires a complex set of properties that can mimic physiological function to create microchip devices. Several factors in the material including the spatial location of the cellular attachment heavily influence the control of this functionality and must be dictated to parallel in vivo characteristics. In this work, we demonstrate polyvinyl alcohol (PVA) for use in emulating these properties to produce a highly robust and functional biomaterial as a microchip. We show the utility of PVA for cellular patterning using soft lithography. Based on these results, PVA can be applied in a diversity of areas including tissue engineering, biomimetics, and cellular micropatterning.

Animals↗
PubMed2006

Update on dermal substitutes.

Tissue-engineered biological dressings offer promise in the treatment of burns, chronic ulcers, donor site and other surgical wounds, and a variety of dermatologic conditions. Despite this promise, cellular tissue-engineered products such a Dermagraft and Apligraf have suffered setbacks in recent years with a lower market share than the commercial promoters of these products anticipated. AlloDerm acellular dermal matrix, an older technology than these cell-based products, has made strong progress in winning over clinicians in various disciplines. Similarly, Integra Bilayer Matrix Wound Dressing (BMWD) continues to gain acceptance beyond its original burn audience. A review on the products is offered.

Chondroitin Sulfates↗
PubMed2005

Embryonic stem cells: a perspective.

Embryonic stem (ES) cells are proliferating tissue-culture cells which are embryonic in origin and retain the full lineage and differentiative capacity of the early mammalian embryo. Only mouse ES cells have been fully characterized but similar cultures have been isolated from numbers of other mammalian embryos including, notably, human. ES cells can differentiate either in vivo in the context of an embryo or equivalently in vitro. Their ability to undergo genetic alteration and selection in vitro followed by embryonic development in vivo has led to their extensive use as a vector for mammalian genetic engineering. This is not an application for human ES cells but their ability to differentiate in vitro into a plethora of specific tissue precursors has led to scenarios for their use in cellular and tissue engineering therapies. Ethical and practical problems for the provision of ad hominem human ES cells remain. Knowledge from the mouse system may aid our understanding of the relationship between ES cells and embryos.

Animals↗
PubMed2002

Potentiation of Fas-mediated apoptosis by an engineered glycosylphosphatidylinositol-linked Fas.

FasL and TRAIL are apoptotic ligands of the TNF-like cytokines family, acting via activation of the transmembrane death domain containing receptors Fas for FasL, and DR4 or DR5 for TRAIL. A glycosylphosphatidylinositol-linked TRAIL receptor called DcR1 behaves as a decoy receptor inhibiting TRAIL-mediated cell death in several cellular systems. We engineered and stably expressed a chimeric GPI-linked Fas receptor (Fas-GPI) in T-lymphocyte cell lines constitutively expressing functional transmembrane Fas. Surprisingly, despite lacking the death domain region of functional Fas, Fas-GPI was able to significantly increase Fas-mediated cell death triggered by membrane bound or soluble FasL, whereas engagement of Fas-GPI alone did not trigger apoptosis. This potentiating effect, but not transmembrane Fas activation, was selectively inhibited by protein kinase C activation with phorbol esters, demonstrating that Fas-GPI activated a specific synergistic signal transduction pathway. Fas-GPI and transmembrane Fas were localized in distinct membrane compartments, since Fas-GPI, but not transmembrane Fas, was found in the glycolipid-rich membrane microdomains. These results suggest that apoptosis induced by members of this ligand/receptors family may be differentially modulated through other and parallel signalling pathways.

Animals↗
PubMed2000

Noise-based switches and amplifiers for gene expression.

The regulation of cellular function is often controlled at the level of gene transcription. Such genetic regulation usually consists of interacting networks, whereby gene products from a single network can act to control their own expression or the production of protein in another network. Engineered control of cellular function through the design and manipulation of such networks lies within the constraints of current technology. Here we develop a model describing the regulation of gene expression and elucidate the effects of noise on the formulation. We consider a single network derived from bacteriophage lambda and construct a two-parameter deterministic model describing the temporal evolution of the concentration of lambda repressor protein. Bistability in the steady-state protein concentration arises naturally, and we show how the bistable regime is enhanced with the addition of the first operator site in the promotor region. We then show how additive and multiplicative external noise can be used to regulate expression. In the additive case, we demonstrate the utility of such control through the construction of a protein switch, whereby protein production is turned "on" and "off" by using short noise pulses. In the multiplicative case, we show that small deviations in the transcription rate can lead to large fluctuations in the production of protein, and we describe how these fluctuations can be used to amplify protein production significantly. These results suggest that an external noise source could be used as a switch and/or amplifier for gene expression. Such a development could have important implications for gene therapy.

DNA-Binding Proteins↗