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PubMedDate not supplied

In vivo tissue engineering of bone using poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) and collagen scaffolds.

Porous poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) (PHBV) and calcium phosphate-loaded collagen (CaP-Gelfix) foams were seeded with rat bone marrow stromal cells and implanted into defects created in rat femurs to study in vivo bone formation and to test their suitability for use in bone tissue engineering. At 3 and 6 weeks, new bone formation was evaluated by macroscopy, radiography, dual-energy X-ray absorptiometry (DEXA), and quantitative computerized tomography (QCT). Atomic contents of the implants were further assessed by QCT. Some initial inflammation that significantly decreased with time was observed in the CaP-Gelfix group. PHBV inflammation was minimal at all stages. Fibrous tissue formation in the CaP-Gelfix group was more than in the PHBV group. Both cell-loaded and cell-free PHBV matrices elicited minimal fibrous tissue formation during the 6-week implantation duration. Macroscopic and radiological studies demonstrated better healing with PHBV matrices than with CaP-Gelfix in 3 weeks. Histologically, fibrous connective tissue establishment and inflammation scores were significantly higher in the CaP-Gelfix group when compared with the PHBV group at both time intervals. At 6 weeks, however, the extent of healing was almost the same with both implants. DEXA and QCT results indicated that there was an increase in bone mineral density in both PHBV and CaP-Gelfix implants at the end of 6 weeks. This study suggests that even though PHBV and CaP-Gelfix have different bulk and surface chemistries they both are promising cell carriers that may be suitable for use in bone tissue engineering.

Animals↗
PubMedDate not supplied

Engineered osteochondral grafts using biphasic composite solid free-form fabricated scaffolds.

Tissue engineering has provided an alternative to traditional strategies to repair cartilage damaged by injury or degenerative disease. A successful strategy to engineer osteochondral tissue will mimic the natural contour of the articulating surface, achieve native mechanical properties and functional load-bearing ability, and lead to integration with host cartilage and underlying subchondral bone. Image-based design (IBD) and solid free-form (SFF) fabrication can be used to generate scaffolds that are load bearing and match articular geometry. The objective of this study was to utilize materials and biological factors in an integrated approach to regenerate a multitissue interface. Biphasic composite scaffolds manufactured by IBD and SFF fabrication were used to simultaneously generate bone and cartilage in discrete regions and provide for the development of a stable interface between cartilage and subchondral bone. Poly-L-lactic acid/hydroxyapatite composite scaffolds were differentially seeded with fibroblasts transduced with an adenovirus expressing bone morphogenetic protein 7 (BMP-7) in the ceramic phase and fully differentiated chondrocytes in the polymeric phase. After subcutaneous implantation into mice, the biphasic scaffolds promoted the simultaneous growth of bone, cartilage, and a mineralized interface tissue. Within the ceramic phase, the pockets of tissue generated included blood vessels, marrow stroma, and adipose tissue. This combination of IBD and SFF-fabricated biphasic scaffolds with gene and cell therapy is a promising approach to regenerate osteochondral defects.

Animals↗
PubMedDate not supplied

Coculture of mesenchymal stem cells and respiratory epithelial cells to engineer a human composite respiratory mucosa.

In this study, we describe a novel in vitro reconstitution system for tracheal epithelium that could be useful for investigating the cellular and molecular interaction of epithelial and mesenchymal cells. In this system, a Transwell insert was used as a basement membrane on which adult bone marrow mesenchymal stem cells (MSCs) were cultured on the lower side whereas normal human bronchial epithelial (NHBE) cells were cultured on the opposite upper side. Under air-liquid interface conditions, the epithelial cells maintained their capacity to progressively differentiate and form a functional epithelium, leading to the differentiation of mucin-producing cells between days 14 and 21. Analysis of apical secretions showed that mucin production increased over time, with peak secretion on day 21 for NHBE cells alone, whereas mucin secretion by NHBE cells cocultured with MSCs remained constant between days 18 and day 25. This in vitro model of respiratory epithelium, which exhibited morphologic, histologic, and functional features of a tracheal mucosa, could help to understand interactions between mesenchymal and epithelial cells and mechanisms involved in mucus production, inflammation, and airway repair. It might also play an important role in the design of an composite prosthesis for tracheal replacement.

Bioartificial Organs↗
PubMedDate not supplied

Repair of large articular cartilage defects with implants of autologous mesenchymal stem cells seeded into beta-tricalcium phosphate in a sheep model.

Tissue engineering has long been investigated to repair articular cartilage defects. Successful reports have usually involved the seeding of autologous chondrocytes into polymers. Problems arise because of the scarcity of cartilage tissue biopsy material, and because the in vitro expansion of chondrocytes is difficult; to some extent, these problems limit the clinical application of this promising method. Bone marrow-derived mesenchymal stem cells (MSCs) have been proved a potential cell source because of their in vitro proliferation ability and multilineage differentiation capacity. However, in vitro differentiation will lead to high cost and always results in decreased cell viability. In this study we seeded culture-expanded autologous MSCs into bioceramic scaffold-beta-tricalcium phosphate (beta-TCP) in an attempt to repair articular cartilage defects (8 mm in diameter and 4 mm in depth) in a sheep model. Twenty-four weeks later, the defects were resurfaced with hyaline-like tissue and an ideal interface between the engineered cartilage, the adjacent normal cartilage, and the underlying bone was observed. From 12 to 24 weeks postimplantation, modification of neocartilage was obvious in the rearrangement of surface cartilage and the increase in glycosaminoglycan level. These findings suggest that it is feasible to repair articular cartilage defects with implants generated by seeding autologous MSCs, without in vitro differentiation, into beta-TCP. This approach provides great potential for clinical applications.

Animals↗
PubMedDate not supplied

Repair of osteochondral defects with autologous chondrocytes seeded onto bioceramic scaffold in sheep.

At present, the most popular biomaterials used in cartilage tissue engineering are synthetic polymers. However, problems-such as acidic by-product accumulation and side effects in local or systemic inflammatory reactions during in vivo degradation-are drawing much attention. The polymers are also highly hydrophobic and degrade within 4 weeks, allowing insufficient time to support neocartilage formation. All these have made polymers less promising in clinical application. In this study, we tested a new bioceramic scaffold made of artificial synthesized powder of beta-tricalcium phosphate (beta-TCP) in a sheep model. Osteochondral defects were filled with a bioceramic-chondrocyte construct and neocartilage tissue completely resurfaced the cartilage defects after 24 weeks. Typical hyaline cartilage structure was generated in the engineered cartilage. Biodegradation of bioceramic was notable, leading to bioceramic fragmentation and particle formation. Numerous ceramic particles (size, 0.5-1.9 microm) and numerous macrophages were observed at the ceramic-tissue interface as well as in the marrow tissue. No macrophages were visible in the neocartilage tissue. Although long-term in vivo study is needed to further determine the pathological sequences of the beta-TCP-based cartilage construct, this study suggests that this bioceramic might be used to repair chondral or osteochondral defects and could be used as a scaffold for cartilage tissue engineering.

Animals↗
PubMed2006

Tissue engineered epithelial cell sheets for the creation of a bioartificial trachea.

To successfully engineer a bioartificial tracheal replacement, it is believed that the regeneration of a functional epithelial lining is a key requirement. In the present study, rabbit tracheal epithelial cells were cultured on temperature-responsive culture dishes, under normal culture conditions at 37 degrees C. By simple temperature reduction to 20 degrees C, the cultured epithelial cells were noninvasively harvested as intact sheets, without the use of any proteolytic enzymes. Support Dacron grafts that had been subcutaneously implanted for 4 weeks to allow for host tissue and vessel infiltration were then opened, and the tracheal epithelial cell sheets were transplanted to the luminal surface without sutures. These fabricated constructs were then used as tracheal replacements, in a rabbit model. Four weeks after transplantation, results showed that the tracheal grafts were covered by a mature, pseudostratified columnar epithelium. In contrast, control constructs that did not receive cell sheet transplantation demonstrated only a thin, immature epithelium at the center of the replacement graft. These results therefore demonstrate that these tracheal epithelial cell sheets can create an epithelial lining on the luminal surface of a bioartificial trachea.

Animals↗
PubMed2006

Direct freeform fabrication of seeded hydrogels in arbitrary geometries.

A major challenge in tissue engineering is the generation of cell-seeded implants with structures that mimic native tissue, both in anatomic geometries and intratissue cell distributions. By combining the strengths of injection molding tissue engineering with those of solid freeform fabrication (SFF), three-dimensional (3-D) pre-seeded implants were fabricated without custom-tooling, enabling efficient production of patient-specific implants. The incorporation of SFF technology also enabled the fabrication of geometrically complex, multiple-material implants with spatially heterogeneous properties that would otherwise be challenging to produce. Utilizing a custom-built robotic SFF platform and gel deposition tools, alginate hydrogel was used with calcium sulfate as a crosslinking agent to produce pre-seeded living implants of arbitrary geometries. The process was determined to be sterile and viable at 94 +/- 5%. The GAG and hydroxyproline production was found to be similar to that of other implants fabricated using the same materials with different shaping methods. The geometric fidelity of the process was quantified by using the printing platform as a computerized measurement machine (CMM); the RMS surface roughness of printed samples in the z-dimension was found to be 0.16 +/- 0.02 mm.

Alginates↗
PubMed2006

A newly developed bioartificial pancreas successfully controls blood glucose in totally pancreatectomized diabetic pigs.

Construction of a safe and functional bioartificial pancreas (BAP) that provides an adequate environment for islet cells may be an important approach to treating diabetic patients. Various types of BAP devices have been developed, but most of them involve extravascular implantation of islets in microcapsules or diffusion chambers. These devices have poor diffusive exchange between the islets and blood, and often rupture. To overcome these problems, we developed a new type of BAP composed of polyethylene-vinyl alcohol (EVAL) hollow fibers that are permeable to glucose and insulin and a poly-amino-urethane-coated, non-woven polytetrafluoroethylene (PTFE) fabric that allows cell adhesion. Porcine islets attached to the surface of the PTFE fabric, but not to the surface of the EVAL hollow fibers, allowing nutrient and oxygen exchange between blood flowing inside the fibers and cells outside. We inoculated this BAP with porcine islets and connected it to the circulation of totally pancreatectomized diabetic pigs. We found that blood glucose levels were reduced to a normal range and general health was improved, resulting in longer survival times. In addition, regulation of insulin secretion from the BAP was properly controlled in response to glucose both in vitro and in vivo. These results indicate that our newly developed BAP may be a potential therapy for the treatment of diabetes in humans.

Animals↗
PubMed2006

Effect of fibroblasts on tracheal epithelial regeneration in vitro.

Several artificial grafts for covering deficient trachea have been produced through tissue engineering. Recently, our group clinically used an artificial trachea made from collagen sponge for patients with noncircumferential tracheal resection. However, the slowness of epithelial regeneration on the surface of the artificial trachea was confirmed as one particular problem. In this study, we co-cultured tracheal epithelial cells with fibroblasts and examined effects of fibroblasts on epithelial regeneration in vitro. Fibroblasts activated epithelial cell proliferation and migration. In co-culture with fibroblasts, epithelial cells reconstructed pseudostratified epithelium, which was composed of ciliated, goblet, and basal cells. Furthermore, a basement membrane was reconstructed between epithelial cells and fibroblasts, and integrin beta4 was also observed there. Fibroblasts rapidly increased mucin secretion by epithelial cells. These results indicate that stimulatory effects of fibroblasts on epithelial cell migration, proliferation, and differentiation would reduce the time required for covering of epithelial cells on the defect of luminal surface and hasten regeneration of morphologically and functionally normalized epithelium involving the reconstruction of basement membrane.

Animals↗
PubMedDate not supplied

Development of an ambulatory artificial lung in an ovine survival model.

We are developing an artificial lung (AL) as an eventual bridge to lung transplant or recovery. The device is rigidly housed, noncompliant, and has a very low resistance to blood flow. In eight sheep, arterial cannulae were anastomosed end-to-side to the proximal and distal main pulmonary artery, and attached to the AL. A pulmonary artery snare between anastomoses diverted full pulmonary blood flow through the AL. Eight of eight sheep survived the preparation. Mean pressure gradient across the AL was 8 mm Hg (3 Wood units; 8 mm Hg/2.8 L/min). Four of eight sheep tolerated immediate full diversion of blood flow and died at 24 and 40 hours (exsanguination) or 168 and 168 hours (elective sacrifice). Four of eight sheep were intolerant of full flow: two died of right heart failure at <8 hours with full flow through the device (full snare); the other two survived with partial device flow (partial snare), but the device clotted. These two then underwent successful closed-chest cannula thrombectomy and device change-out at 53 and 75 hours, and subsequently tolerated full flow. Long-term (up to 7 day) survival with complete diversion of pulmonary blood flow through a non-compliant, low-resistance AL is possible. Initial right heart failure in this model was 50% (4 of 8).

Ambulatory Care↗
PubMed2001

Intraoral wound closure with tissue-engineered mucosa: new perspectives for urethra reconstruction with buccal mucosa grafts.

In urethra reconstruction, the creation of a new urethra from a free oral mucosa graft is an established surgical technique. The oral mucosa is removed at the same time that the urethra reconstruction procedure is performed. Depending on the size of graft required, the intraoral wound is closed primarily or left to heal secondarily. The latter method limits this technique by leading to scars or strictures, which have a negative impact on the condition of the intraoral soft tissue. Therefore, in this study, a pilot study involving 12 patients, tissue-engineered mucosa was tested for covering intraoral defects to avoid the drawbacks mentioned above. For mucosa tissue-graft engineering, a biopsy sample 2 to 4 mm in diameter was removed from the hard palate approximately 4 weeks before the urethra reconstruction procedure was to be performed. In addition, 30 ml of autogenous serum was extracted from a venous whole-blood sample. The primary cultures were incubated in Dulbecco modified Eagle's medium and nutrient factor F 12 (Gibco Co., Eggenstein, Germany), containing the usual additives and autogenous serum. After a period of 3 weeks, subcultivation was performed to engineer mucosa transplants consisting of several layers of keratinocytes on a support foil. After thorough intraoperative blood coagulation had occurred, the cultured mucosa graft on the carrier foil was applied on the wound surface and fixed by single sutures. Additionally, the cultured mucosa graft was covered for 8 to 10 days by an intraoral dressing, which was also fixed onto the wound surface by single suture loops. It is possible to perform primary intraoral wound closure with tissue-engineered mucosa to cover defect sizes as large as 11.0 x 4.0 cm. This new method provides a better prospect for both urethra reconstruction and the reconstruction of intraoral tissue defects. The number and size of intraoral scars and strictures are diminished. This is of special interest for the reconstruction of the functional unit oral cavity, including soft tissue and cosmetic conditions (e.g., in case of prosthetic rehabilitation). In comparison to primary wound closure with local tissue, the technique presented in this study reduces the severity of postoperative pain and allows faster rehabilitation in patients because of a better wound-healing process. Furthermore, better mobility of intraoral soft tissue structures is achieved.

Adolescent↗
PubMed2001

Take percentage and conditions of cultured epithelium were improved when basement membrane of the graft was maintained and anchoring mesh was added.

To achieve a higher take rate for epithelial grafts, this study investigated grafting techniques. Seventy-seven nude mice received flap grafting in which cultured human epithelium was grafted inside the flap, and 55 nude rats received transplantation of epithelium to a full-thickness skin defect. In each group, four models were studied, including model 1, in which epithelium was cultured with the conventional method; model 2, in which epithelium was cultured with fibrin gel to avoid sheet damage, then absorptive mesh was incorporated into the epithelium for anchoring to the graft bed; model 3, in which epithelium was cultured with fibrin gel and combined with absorptive mesh and artificial dermis containing fibroblasts; and model 4, in which the model 2 epithelium was grafted after artificial dermis was transplanted. The take for these models was evaluated grossly and histologically. The results show that the take percentage of models 2 and 3 was significantly higher than that of model 1 (conventional epithelium) and that there was no significant difference between model 3 (simultaneous grafting) and model 4 (two-step grafting). The difference in the take percentages of the grafts to the flap and to the full-thickness skin defect was also insignificant. In immunohistochemistry, human keratin appeared in all epidermis layers and diversification of the layer was observed in models 2, 3, and 4. In these three models, type IV collagen appeared in the basal layer and the formation of basal membrane was confirmed. These findings suggest that epithelia cultured on fibrin gel and combined with absorptive mesh could be used in a new technique for better, more stable take.

Absorbable Implants↗
PubMed2004

The efficient prevascularization induced by fibroblast growth factor 2 with a collagen-coated device improves the cell survival of a bioartificial pancreas.

OBJECTIVES: The subcutaneous transplantation of a bioartificial pancreas is a very attractive cure for diabetes mellitus. We recently developed a new immunoisolatory device that has the ability to induce neovascularization for subcutaneous transplantation. We applied the newly developed device to subcutaneous transplantation of a bioartificial pancreas. METHODS: We investigated the prevascularization-inducing activity of the device in diabetic rats by histologic analysis and evaluated the permeability of the device to insulin and BSA. We also evaluated the survival of cells enclosed in a bioartificial pancreas, which was composed of the device, from the viewpoint of the effects of prevascularization by semiquantitative RT-PCR. RESULTS: The devices induced prevascularization more efficiently than fibroblast growth factor 2 impregnated in gelatin microspheres alone did and had more useful permeability than a noncollagen-coated device. Significantly higher expression of insulin mRNA was detected in the RT-PCR amplicons from cells retrieved from the bioartificial pancreas transplanted at the prevascularization-induced site as compared with at a nonprevascularization-induced site. CONCLUSION: We demonstrated that our newly developed device has a superior ability to induce prevascularization in diabetic rats, and the prevascularization improves the initial cell survival of the implanted cells following transplantation.

Animals↗
PubMed2003

Bioartificial kidney ameliorates gram-negative bacteria-induced septic shock in uremic animals.

The bioartificial kidney (BAK) consists of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) porcine renal proximal tubule cells. BAK replaces filtration, transport, and metabolic and endocrinologic activities of a kidney. Previous work in an acutely uremic dog model demonstrated that BAK ameliorated endotoxin (lipopolysaccharide [LPS])-induced hypotension and altered plasma cytokine levels. To further assess the role of BAK in sepsis in acute renal failure, dogs were nephrectomized and 48 h later administered intraperitoneally with 30 x 10(10) bacteria/kg of E. coli. One hour after bacterial administration, animals were placed in a continuous venovenous hemofiltration circuit with either a sham RAD without cells (n = 6) or a RAD with cells (n = 6). BP, cardiac output, heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance were measured throughout the study. All animals tested were in renal failure, with blood urea nitrogen and serum creatinine concentrations greater than 60 and 6 mg/dl, respectively. RAD treatment maintained significantly better cardiovascular performance, as determined by arterial BP (P < 0.05) and cardiac output (P < 0.02), for longer periods than sham RAD therapy. Consistently, all sham RAD-treated animals, except one, expired within 2 to 9 h after bacterial administration, whereas all RAD-treated animals survived more than 10 h. Plasma levels of TNF-alpha, IL-10, and C-reactive protein (CRP) were measured during cell RAD and sham RAD treatment. IL-10 levels were significantly higher (P < 0.01) during the entire treatment interval in the RAD animals compared with sham controls. These data demonstrated in a pilot large animal experiment that the BAK with RAD altered plasma cytokine levels in acutely uremic animals with septic shock. This change was associated with improved cardiovascular performance and increased survival time. These results demonstrate that the addition of cell therapy to hemofiltration in an acutely uremic animal model with septic shock ameliorates cardiovascular dysfunction, alters systemic cytokine balance, and improves survival time.

Animals↗
PubMed2005

Evaluation of renal function and upper urinary tract morphology in the ileal orthotopic neobladder with no antireflux mechanism.

PURPOSE: Long-term renal function is crucial in orthotopic bladder substitutions, and can be influenced by several factors including ureteral obstruction, urinary infection and reflux. In this study we investigated the prevalence of renal functional impairment and the incidence of morphological alterations of the upper urinary tract in patients who had a low pressure ileal neobladder constructed with no antireflux mechanism. MATERIALS AND METHODS: From 1996 to 2002, 70 men received a W-shaped neobladder using refluxing ureterointestinal anastomoses and short afferent limb. Final evaluation of patient status was in November 2003. A total of 20 patients died during followup and mean followup of the remaining 50 patients was 50 months (range 21 to 89). Kidney morphology was evaluated using technetium diethylenetetraminepentaacetic acid nuclear renography and ultrasonography. Total and separate renal function were evaluated by measuring plasma creatinine and glomerular filtration rate (GFR), the latter measured as the renal clearance of technetium diethylenetetraminepentaacetic acid. Measured values of GFR were compared with the results from a group of healthy subjects of the same age. RESULTS: The anastomotic stricture rate was 4%, 2 severe strictures occurred 2 and 4 months after surgery, while 2 moderate strictures were detected with renal scans during the study. Renal scintigraphy revealed an excretory phase within the normal range in 67 of 99 renoureteral units (68%), a short delay in collecting system drainage associated with mild and transient pelvicaliceal dilatation in 23 (23%), and dilatation of the upper urinary tract in the remaining 9 (9%) including obstructive in 2 (2%) and not obstructive in 7 (7%). Mean (+SD) total GFR of the patients was 89.7 (19.6) ml per minute per 1.73 m. Mean total GFR of the control group was 90.6 (11.4) ml per minute per 1.73 m. The comparison between measured GFR of patients and the control group showed no statistically significant difference. CONCLUSIONS: Our medium-term data support the assumption that the lack of any antireflux mechanism in orthotopic neobladder, per se, has no detrimental effect on renal function.

Aged↗
PubMed2006

Effect of rat-to-mouse bioartificial pancreas xenotransplantation on diabetic renal damage and survival.

OBJECTIVE: Diabetic nephropathy is a life-threatening complication of diabetes mellitus. Bioartificial pancreas transplantation is becoming a therapeutic option for diabetes mellitus as it protects both allogeneic and xenogeneic islets from the host immune system. This study was undertaken to determine the effectiveness of bioartificial pancreas transplantation to improve or prevent diabetic renal damage. METHODS: Approximately 800 rat islets were macroencapsulated in polyvinyl alcohol gel and then transplanted into the peritoneal cavity of diabetic mice (transplantation group [Tx group]). Diabetic mice transplanted with a capsule without islets served as a sham operation group. After transplantation, the following data were collected: survival, body weight, blood glucose, blood urea nitrogen, serum creatinine levels, urinalysis, water intake, and histological changes in the kidney. RESULTS: There was a significant improvement in survival, blood glucose, blood urea nitrogen, and creatinine in the Tx group compared with the sham operation group. No remarkable changes were seen in urinary parameters between the 2 groups, and there was also no significant difference in water intake. Histological examination revealed that mesangial matrix expansion was decreased in the Tx group. CONCLUSIONS: This study demonstrated that polyvinyl alcohol gel bioartificial pancreas transplantation can protect the kidney from diabetic damage.

Animals↗
PubMed2006

Tissue-engineered axially vascularized contractile skeletal muscle.

BACKGROUND: As tissue-engineered muscle constructs increase in scale, their size is limited by the need for a vascular supply. In this work, the authors demonstrate a method of producing three-dimensional contractile skeletal muscles in vivo by incorporating an axial vascular pedicle. METHODS: Primary myoblast cultures were generated from adult F344 rat soleus muscle. The cells were suspended in a fibrinogen hydrogel contained within cylindrical silicone chambers, and situated around the femoral vessels in isogeneic adult recipient rats. The constructs were allowed to incubate in vivo for 3 weeks, at which point they were explanted and subjected to isometric force measurements and histologic evaluation. RESULTS: The resulting three-dimensional engineered skeletal muscle constructs produced longitudinal contractile force when electrically stimulated. Length-tension, force-voltage, and force-frequency relationships were similar to those found in developing skeletal muscle. Desmin staining demonstrated that individual myoblasts had undergone fusion to form multinucleated myotubes. Von Willebrand staining showed that the local environment within the chamber was richly angiogenic, and capillaries had grown into and throughout the constructs from the femoral artery and vein. CONCLUSIONS: Three-dimensional, vascularized skeletal muscle can be engineered in vivo. The resulting tissues have histologic and functional properties consistent with native skeletal muscle.

Animals↗