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Background: Collagen, a critical structural protein found abundantly in animal skin and bones, has become increasingly recognized for its potential therapeutic role in skincare. Despite growing interest, the scientific evidence for the efficacy of collagen sheet masks remains limited. The principal objective of our study was to provide insights into the multifaceted role of collagen in skin health, with a specific focus on its application in collagen sheet masks., Methods: The effects of a collagen sheet mask consisting of >92% native bovine collagen were investigated. The soluble protein components of the collagen matrix were analyzed and the influence of soluble collagen components on fibroblast regulation was examined. Scanning Electron Microscope (SEM) analysis was performed for structural analysis and effect on irritated skin. Five different clinical studies were conducted, including a comparison of the diversity of the skin microbiome, the tolerance and local irritating reactions in atopic dermatitis, an evaluation of skin redness after UV radiation, wrinkle reduction, and hydration and skin roughness of the collagen mask in comparison to a pre-soaked cellulose sheet mask., Results: The collagen mask contains soluble protein components, including small collagen peptides. The mask showed potential for promoting fibroblast activity. SEM analysis showed a native collagen structure similar to human dermis. The mask maintained the skin microbiome diversity and decreased skin pH levels. It demonstrated good tolerability on both intact and lesional skin and had a significant effect in reducing erythema caused by UV radiation compared to other skincare products. It showed significant improvements in skin hydration and the volume of eye wrinkles and was more effective than pre-soaked cellulose sheet masks., Conclusion: Collagen sheet masks have the potential to positively impact skin health and appearance by increasing hydration, reducing erythema, minimizing wrinkles, and maintaining a healthy skin microbiome and skin barrier., (© 2024 MedSkin Solutions Dr. Suwelack AG. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Choice of appropriate biomaterial is a key factor for the success of recombinant human bone morphogenetic protein (rhBMP)-2 therapy. Inspired by osteogenic cell-differentiating and osteoclast-suppressing capabilities of alendronate (ALN), we manufactured a composite type of ALN-loaded collagen sponge (ALN-CS), which controls the early detrimental effect of high-dose rhBMP-2. This study aimed to evaluate ALN-CS as a high-dose rhBMP-2 carrier by investigating its initial biomolecular effect and efficacy on intramembranous ossification at 1, 4, 8, and 24 weeks using a rat calvarial defect model compared with nonloaded CS. The in vitro rhBMP-2 release in the ALN-CS showed a low initial burst and steady release phase during the rest period despite lack of calcium compared with that in CS alone. ALN release showed the same tendency as rhBMP-2 release. In vitro characterization showed that osteoblast differentiation and mineralization of mesenchymal stromal cells were more enhanced with ALN-CS. The ALN-CS-BMP group showed higher expression of bone-forming and -resorbing markers in vivo than the CS-BMP group after the first 7 days, which might be attributable to the relatively large amount of rhBMP-2 remaining. However, osteoclast activation in the ALN-CS-BMP group was significantly reduced compared with the CS-BMP group. Radiological and histological analyses revealed that ALN-CS-BMP promoted early and dense ossification at the initial defect, with 100% greater bone mass, 20% greater bone density, and less fatty marrow tissue than CS-BMP, which continued during the whole healing period. However, CS or ALN-CS alone failed to show complete defect closure even at the 24-week healing interval. Our results demonstrate that ALN-CS has remarkable advantages over CS alone in high-dose BMP-2 delivery, with potent suppression of resorption, early and dense ossification at the target area with less fatty marrow formation, and continuation of bone quality over the long term, which highlights its great clinical potential as a rhBMP carrier for bone regeneration at intramembranous ossification sites.

Background: Collagen exhibits ideal multifactorial action for preventing tissue adhesions. This study examined the efficacy of ionized collagen in preventing tissue adhesion after surgical procedures., Materials and Method: Ionized collagen was prepared using the esterification technique of natural collagen. Three forms of collagen materials (membrane, film, and gel) were compared with three commercialized materials (oxidized regenerated cellulose membrane [OC membrane], hyaluronic acid and carboxymethylcellulose film, and gel [HC film and HC gel]) in a rat cecum abrasion model. Antiadhesive activity and histologic findings were assessed., Result: The incidence of adhesion was reduced significantly in all test groups compared to the sham-operated control group (100% in control, 14.3% in collagen membrane, 63.6% in collagen film, 25.0% in collagen gel, 55.6% in OC membrane, 75% in HC film, and 83.3% in HC gel). All collagen materials of the three forms exhibited a significant reduction in adhesion grade compared with the sham operation, whereas no significant difference was found among these three different forms. The collagen membrane showed significantly less adhesion grade, less inflammation and more regenerative features compared to widely used conventional materials., Conclusions: This preclinical investigation indicated that ionized collagen materials readily formed clinically suitable shapes for easy handling without the need for any complex processing and effectively reduced postoperative tissue adhesion profiles compared to conventional antiadhesive agents., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sustained release of bone morphogenetic protein (BMP)-2 by heparin-contained biomaterials is advantageous for bone tissue regeneration using low-dose BMP-2. However, its effect with high-dose BMP-2 is still unclear and should be clarified considering the clinical use of a high dose of BMP-2 in spine and oral surgery. This study aimed to evaluate the efficacy of a heparin-conjugated collagen sponge (HCS) with high-dose BMP-2 delivery by investigating in vivo initial osteogenic regulation and bone healing over 12 weeks in comparison with that of an absorbable collagen sponge (ACS). The in vitro BMP-2 release profile in the HCS exhibited a lower burst followed by a sustained release of BMP-2, whereas that of the ACS showed an initial burst phase only. As a result of a lower burst, the HCS-BMP group showed higher expression of bone-forming/resorbing markers and enhanced activation of osteoclasts than the ACS-BMP group within the scaffold of defect after 7 days, which is presumed to be because of retention of relatively higher amounts of BMP-2. However, the surrounding calvariae were less resorbed in the HCS-BMP group, compared with the aggressive resorptive response in the ACS-BMP group. Microcomputed tomography and histology revealed that HCS-BMP guided more effective bone regeneration of central defect over time inducing minor ossification at the defect exterior, whereas ACS-BMP exhibited excessive ossification at the defect exterior. These results showed that HCS-mediated BMP-2 delivery at a high dose has advantages over ACS, including less early resorption of surrounding bone tissue and higher efficacy in compact bone regeneration over a longer period, highlighting a clinical feasibility of this technology.

Collagen, one of the most important components of the extracellular matrix (ECM), may play a role in the survival of pancreatic islet cells. In addition, chemical modifications that change the collagen charge profile to a net positive charge by esterification have been shown to increase the adhesion and proliferation of various cell types. The purpose of this study was to characterize and compare the effects of native collagen (NC) and esterified collagen (EC) on β cell function and survival. After isolation by the collagenase digestion technique, rat islets were cultured with NC and EC in 2 dimensional (2D) and 3 dimensional (3D) environments for a long-term duration in vitro. The cells were assessed for islet adhesion, morphology, viability, glucose-induced insulin secretion, and mRNA expression of glucose metabolism-related genes, and visualized by scanning electron microscopy (SEM). Islet cells attached tightly in the NC group, but islet cell viability was similar in both the NC and EC groups. Glucose-stimulated insulin secretion was higher in the EC group than in the NC group in both 2D and 3D culture. Furthermore, the mRNA expression levels of glucokinase in the EC group were higher than those in the NC group and were associated with glucose metabolism and insulin secretion. Finally, SEM observation confirmed that islets had more intact component cells on EC sponges than on NC sponges. These results indicate that modification of collagen may offer opportunities to improve function and viability of islet cells., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Study Design: In vitro experiment using rabbit nucleus pulposus (NP) cells seeded in atelocollagen scaffolds under the stimulation of growth factors., Objective: To demonstrate the effect of anabolic growth factors in rabbit NP cells cultured in atelocollagen type I and type II., Summary of Background Data: Atelocollagen provides intervertebral disc (IVD) cells for a biocompatible environment to produce extracellular matrix. IVD cells with exogenous transforming growth factor-beta 1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) also render an increase in matrix synthesis. However, the effect of anabolic growth factors in NP cells cultured in atelocollagens was not elucidated before., Methods: Rabbit NP cell was harvested, enzymatically digested, and cultured. The NP cells were seeded to atelocollagen type I and type II scaffolds, and then cultures were exposed to TGF-β1 (10 ng/mL) and/or BMP-2 (100 ng/mL). DNA synthesis was measured using [4H]-thymidine incorporation. Newly synthesized proteoglycan was measured using [35S]-sulfate incorporation. Reverse transcription-polymerase chain reactions (RT-PCRs) for mRNA expression of aggrecan, collagen type I, collagen type II, and osteocalcin were performed., Results: Rabbit NP cells cultured in atelocollagen type I scaffold showed an increase (1.7 to 2.4-fold) in DNA synthesis in response to TGF-β1 and/or BMP-2 (P < 0.05), whereas NP cultures in atelocollagen type II demonstrated a 30% increase in DNA synthesis only with combination of both growth factors compared with control (P < 0.05). Rabbit NP cells in atelocollagen type II scaffold with TGF-β1 and combination of both growth factors exhibited robust 5.3- and 5.4-fold increases in proteoglycan synthesis (P < 0.05), whereas any cultures in atelocollagen type I failed to show any significant increase compared with control. Rabbit NP cells in atelocollagen type I and type II scaffolds with TGF-β1 and/or BMP-2 demonstrated the upregulation of aggrecan, collagen type I, and collagen type II mRNA expression compared with saline control (P < 0.05). The response in transcriptional level was more robust in atelocollagen type II than in type I. In any event, there is no recognizable expression of osteocalcin (P < 0.05)., Conclusion: NP cells in atelocollagens under the stimulation of TGF-β1 and BMP-2 exhibited anabolic responses in transcriptional and translational levels. Hence, such an approach can provide a suitable engineered tissue for IVD regeneration with potential for robust refurbishment of matrix.

Background: Commercially available hemostatic-adhesive has the risk of disease transmission because it is derived from a plasma component. The purpose of this study is to manufacture a new hemostatic adhesive and evaluate its performances., Methods: Two atelocollagen-based hemostatic adhesives were produced and named as Bleestop A (2% esterified atelocollagen in 75% ethanol + 1% CaCl(2) + 0.71% DOPA + 0.1% tranexamic acid in DW) and Bleestop B (2% esterified atelocollagen in DW + 1% CaCl(2) + 0.71% DOPA + 0.1% aminocaproic acid in DW). These are compared with the negative control group (no adhesives used group) and the positive control group (Tissucol Duo Quick group). The adult male Sprague-Dawley rat model was adopted and the hemostatic-adhesion activities of each group were assessed by the adhesion strength test and the morphologic features of adhesion. The liver tissues were used. Histologic assessment of adhesion was accessed using light microscopy., Results: Bleeding was controlled immediately after application of Bleestop A and partial adhesion was observed after 30 s. More than 95% area of the resected surface attached after 1 min. In Bleestop B, partial adhesion was observed after 30 s. More than 95% area of the resected surface was attached after 45 s. Histologic evaluation showed that Bleestop A and B mediated organized adhesion rapidly between both resected tissue surfaces. The adhesion strength of Bleestop A and B was better than the negative control group and showed same adhesion strength as the positive control group after 3 min., Conclusion: Bleestop A and B showed significant hemostasis and adhesion capability within 1 min. They are comparable to the positive control group., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The 1-ethyl-(3-3-dimethylaminopropyl) carbodiimide hydrochloride-crosslinked collagen-hyaluronic acid (HA) matrices containing tobramycin or ciprofloxacin as an antibiotic agent were fabricated for the control of wound contamination and characterized with respect to morphology, mechanical strength, in vitro release, antibacterial activity and cytotoxicity. For the tobramycin loaded matrix, the antibacterial capacity increased with the drug loading. Tobramycin and ciprofloxacin loaded matrices maintained their antibacterial effects for over 96 and 48 h, respectively. However, cell viability testing revealed that 0.4 mg/ml of ciprofloxacin has a cytotoxic effect on fetal human dermal fibroblasts. The effects of the bilayered collagen-HA matrices containing tobramycin and growth factors were also evaluated using an in vivo full thickness dermal defect model. Though the tobramycin incorporated collagen-HA matrix had no significant effect on wound healing compared with the control, the tobramycin incorporated matrix containing basic fibroblast growth factor or platelet-derived growth factor significantly enhanced wound healing. This study demonstrates the potential efficacy of crosslinked collagen-HA matrix containing antibiotics and growth factors for defective skin tissue replacement and infection prevention.

Porous collagen matrices crosslinked with various amounts of hyaluronic acid (HA) by 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC) were developed as scaffolds for dermal tissue regeneration. The effect of HA on cells in accordance with HA concentrations in the collagenous matrices was investigated using cultures of fetal human dermal fibroblasts, and the effect of EDC-crosslinked collagen-HA matrix on wound size reduction was also evaluated in vivo. Scanning electron microscopic views of the matrices demonstrated that all of the collagen-HA matrices had interconnected pores with mean diameters of 150-250 microm. An HA matrix retention test showed that the concentration of HA decreased slowly after an initial rapid decrease over 24h. Fetal human dermal fibroblasts adhered well to all of the collagen-based matrices as compared with the Porous polyurethane matrix used as a control. An 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide based proliferation test and the hematoxylin and eosin staining of a 2 week cultured matrix showed that the proliferation of fibroblasts was enhanced on a 9.6% HA contained collagen matrix. No significant difference was in terms of fibroblast migration into the various types of scaffolds as HA content was increased. In vivo testing showed that dermis treated with collagen or collagen-HA matrix was thicker than the control, and epithelial regeneration was accelerated, and collagen synthesis increased. However, no significant effect of HA on wound size reduction was found.

In order to develop a scaffolding material for tissue regeneration, porous matrices containing collagen and hyaluronic acid were fabricated by freeze drying at -20 degrees C, -70 degrees C or -196 degrees C. The fabricated porous membranes were cross-linked using 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) in a range of 1-100 mM concentrations for enhancing mechanical stability of the composite matrix. Scanning electron microscope (SEM) views of the matrices demonstrated that the matrices obtained before cross-linking process had interconnected pores with mean diameters of 40, 90 or 230 microm and porosity of 58-66% according to the freezing temperature, and also the porous structures after cross-linking process were retained. The swelling test and IR spectroscopic measurement of different cross-linked membranes were carried out as a measure of the extent of cross-linking. The swelling behavior of cross-linked membranes showed no significant differences as cross-linking degree increased. FT-IR spectra showed the increase of the intensity of the absorbencies at amide bonds (1655, 1546, 1458 cm(-1)) compared to that of CH bond (2930 cm(-1)). In enzymatic degradation test, EDC treated membranes showed significant enhancement of the resistance to collagenase activity in comparison with 0.625% glutaraldehyde treated membranes. In cytotoxicity test using L929 fibroblastic cells, the EDC-cross-linked membranes demonstrated no significant toxicity.

Collagen, known for its excellent biocompatibility and biological properties, has limited in vivo maintenance duration after implantation, while hyaluronic acid faces challenges such as various complications and insufficient support for cell proliferation. In this study, an injectable hyaluronic acid/collagen (HCol) hydrogel was developed to achieve enhanced cell-material interactions and accelerated skin regeneration. Physical and chemical characterizations demonstrated that the HCol hydrogel was injectable and stable after the implantation. In vitro cell culture results illustrated that the hydrogel promoted the proliferation of human dermal fibroblasts, extracellular matrix expression and angiogenesis. The subcutaneous implantation in rats showed the superior biocompatibility of HCol hydrogel and enhanced secretion and deposition of extracellular matrix, compared with commercial hyaluronic acid dermal filler. MRI analysis showed that the hydrogel stably remained in vivo for at least three months. The histological examination and SHG signals further demonstrated that the hydrogel modulated fibroblast phenotype and stimulated vascular ingrowth and collagen synthesis, without inducing significant inflammation, swelling or erythema in vivo. [ABSTRACT FROM AUTHOR]

Background: In reconstructive and plastic surgery, split-thickness skin graft (STSG) treatments are frequently used to treat a variety of skin abnormalities. However, managing donor sites is difficult because of issues including infection and delayed recovery. Although collagen-based dressings have showed potential in the field of wound healing, STSG donor sites have not been the subject of indepth research. Methods: 100 patients getting STSG participated in this prospective randomized controlled trial, which was run between December 2020 and June 2022. The collagen dressing group (n = 50) and the standard saline dressing group (n = 50) were randomly assigned to the patients. Secondary outcomes were patient-reported outcomes and cosmetic evaluation, whereas primary results included healing rate and complication incidence. Results: Complete wound closure was achieved by 85% of patients in the collagen dressing group by postoperative day 30, compared to 62% in the regular saline dressing group. This represents a significant improvement in healing rates. When compared to the standard saline dressing group (18%), complications were lower in the collagen dressing group (6%). Patients who received collagen dressings reported less discomfort and greater satisfaction with their wound treatment. The collagen dressing group had better aesthetic results, according to cosmetic evaluation (80% rated "excellent"). Conclusion: At STSG donor sites, collagen dressings dramatically improve healing, lower complications, and enhance patient experiences. The use of collagen dressings in reconstructive and cosmetic surgery is supported by these data, which also point to prospective advantages. For these results to be validated and optimized, more study is required. [ABSTRACT FROM AUTHOR]

Background: Three- dimensional (3D) technology has been suggested to overcome several limitations in guided bone regeneration (GBR) procedures because 3D-printed scaffolds can be easily molded to patient-specific bone defect site. This study aimed to investigate the effect of 3-D printed polylactic acid (PLA) scaffolds with or without hyaluronic acid (HA) in a rabbit calvaria model.Methods: A calvaria defect with a diameter of 15 mm was created in 30 New Zealand white rabbits. The rabbits were randomly allocated into three groups including no graft group (control, n = 10), 3D printed PLA graft group (3D-PLA, n = 10), and 3D printed PLA with hyaluronic acid graft group (3D-PLA/HA, n = 10). Five animals in each group were sacrificed at 4 and 12 weeks after surgery. Microcomputed tomography and histologic and histomorphometric analyses were performed.Results: Over the whole examination period, no significant adverse reactions were observed. There were no statistically significant differences in bone volume (BV) /tissue volume (TV) among the three groups at 4 weeks. However, the highest BV/TV was observed in the 3D-PLA/HA group at 12 weeks. The new bone area for control, 3D-PLA, and 3D-PLA/HA showed no statistical differences at 4 weeks. However, the value was significantly higher in the 3D-PLA and 3D-PLA/HA groups compared to the control group at 12 weeks.Conclusion: The 3D printed PLA scaffolds was biocompatible and integrated well with bone defect margin. They were also provided the proper space for new bone formation. Therefore, 3D printed PLA/HA might be a potential tool to enhance bone augmentation. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) plays an important role in tissue repair, cell proliferation, and differentiation. Our previous study showed that collagen I and collagen V differently regulate the proliferation of rat pancreatic β cells (INS-1 cells) through opposite influences on the nuclear translocation of β-catenin. In this study, we investigated the β-catenin pathway in INS-1 cells on dishes coated with collagen I or V. We found that nuclear translocation of the transcription factor Yes-associated protein (YAP) was enhanced by collagen I and suppressed by collagen V, but had no effect on INS-1 cell proliferation. Morphologically, INS-1 cells on collagen V-coated dishes showed stronger cell-to-cell adhesion, while the cells on collagen I-coated dishes showed weaker cell-to-cell adhesion in comparison with the cells on non-coated dishes. E-cadherin played an inhibitory role in the proliferation of INS-1 cells cultured on collagen I or collagen V coated dishes via regulation of the nuclear translocation of β-catenin. Integrin β1 was enhanced with collagen I, while it was repressed with collagen V. The integrin β1 pathway positively regulated the cell proliferation. Inhibition of integrin β1 pathway restored the protein level of E-cadherin and inhibited the nuclear translocation of β-catenin in the cells on collagen I-coated dishes, but no effect was observed in the cells on collagen V-coated dishes. In conclusion, collagen I enhances the proliferation of INS-1 cells via the integrin β1 and E-cadherin/β-catenin signaling pathway. In INS-1 cells on collagen V-coated dishes, both integrin β1 and E-cadherin/β-catenin signal pathways are involved in the inhibition of proliferation. [ABSTRACT FROM AUTHOR]

Background: Ultraviolet B (UVB) irradiation is viewed as the main factor of skin aging, associated with acceleration of elastin, collagen degradation and expression of matrix metalloproteinases (MMPs). Apples are one of the most commonly eaten fruits in the world, and isoquercitrin is the main active ingredient in new bred varieties "Green ball" apple. Therefore, we are studying the functionality of the active ingredient of apple, a natural raw material that does not have toxicity or sensitivity problems. Objectives: The aim of this study, we scrutinized the effects of isoquercitrin on skin photoaging in UVB‐exposed human fibroblasts (CCD‐986Sk). Methods: To investigate the inhibition effect on photoaging factor regulation, isolated isoquercitrin were treated with UVB, which induces photoaging‐related factors in CCD‐986Sk fibroblast cells. Pro‐inflammatory factors were measured by ELISA, Western blotting and real‐time PCR. Results: Isoquercitrin exhibited antioxidant activity and UVB‐induced generation of photoaging‐related factor inhibition without showing any toxicity. Anti‐photoaging effect for protein levels using Isoquercitin was competent, of both the combate MMP‐1 and MMP‐9. Also, effect of COL1A2 product significantly increase, from up regulating the TIMP‐1 mediated pathway in CCD‐986Sk cells via the inhibition of MMPs. Isoquercitrin also downregulated the mRNA gene expression of MMPs while upregulating type I procollagen, HAS2 by modulating TIMP‐1 and TGF‐β in UVB‐irradiated CCD‐986Sk cells. Conclusions: Collectively, our results show that isoquercitrin might be useful as a functional food while being a good candidate in the development of cosmetic products and medicines for the remedy of UVB‐induced skin photoaging. [ABSTRACT FROM AUTHOR]

Background: Collagen scaffolds are widely used for guided bone or tissue regeneration. Aiming to enhance their regenerative properties, studies have loaded various substances onto these scaffolds. This review aims to provide an overview of existing literature which conducted in vitro, in vivo, and clinical testing of drug-loaded collagen scaffolds and analyze their outcome of promoting oral regeneration. Materials and methods: PubMed, Scopus, and Ovid Medline® were systematically searched for publications from 2005 to 2019. Journal articles assessing the effect of substances on oral hard or soft tissue regeneration, while using collagen carriers, were screened and qualitatively analyzed. Studies were grouped according to their used substance type—biological medical products, pharmaceuticals, and tissue-, cell-, and matrix-derived products. Results: A total of 77 publications, applying 36 different substances, were included. Collagen scaffolds were demonstrating favorable adsorption behavior and release kinetics which could even be modified. BMP-2 was investigated most frequently, showing positive effects on oral tissue regeneration. BMP-9 showed comparable results at lower concentrations. Also, FGF2 enhanced bone and periodontal healing. Antibiotics improved the scaffold's anti-microbial activity and reduced the penetrability for bacteria. Conclusion: Growth factors showed promising results for oral tissue regeneration, while other substances were investigated less frequently. Found effects of investigated substances as well as adsorption and release properties of collagen scaffolds should be considered for further investigation. Clinical relevance: Collagen scaffolds are reliable carriers for any of the applied substances. BMP-2, BMP-9, and FGF2 showed enhanced bone and periodontal healing. Antibiotics improved anti-microbial properties of the scaffolds. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the potential efficacy of purified porcine atelocollagen (PAC) for the management of refractory chronic pain due to suspected connective tissue damage. Methods: Patients treated with PAC were retrospectively evaluated. Patients with chronic refractory pain, suspected to have originated from musculoskeletal damage or defects with the evidence of imaging studies were included. Pain intensity, using the 11-point numerical rating scale (NRS), was assessed before the procedure, and 1 month after the last procedure. Results: Eighty-eight patients were finally included for investigation. The mean NRS score was decreased from 5.8 to 4.1 after 1 month of PAC injection (P < 0.001). No independent factor was reported to be directly related to the decrease in NRS score by more than half. Conclusions: Application of PAC may have potential as a treatment option for refractory chronic musculoskeletal pain. PAC might promote tissue recovery, act as a scaffold for repair, or directly reduce inflammation. [ABSTRACT FROM AUTHOR]

Here, we demonstrated the fabrication of a composite scaffold (chitosan [CS], collagen [Col], and hydroxyapatite [HA]) with the incorporation of encapsulated Cissus quadrangularis (CQ) extract for tissue engineering applications. First, the crude extract of CQ loaded nanoparticles were synthesized via double emulsion technique using polycaprolactone (PCL) and polyvinyl alcohol (PVA) as oil and aqueous phases, respectively. Both PCL (20, 40, and 80 mg/mL) and PVA (0.5%, 1%, and 3% w/v) concentrations were varied to determine the optimum concentrations for CQ‐loaded nanoparticle preparation. The CQ‐loaded PCL nanoparticles (CQ‐PCL NPs), prepared with 20 mg/mL PCL and 0.5% (w/v) PVA, exhibited the smallest size of 334.22 ± 43.21 nm with 95.54 ± 1.49% encapsulation efficiency. Then, the CQ‐PCL NPs were incorporated into the CS/Col/HA scaffolds. These scaffolds were also studied for their ultrastructure, pore sizes, chemical composition, compressive modulus, water swelling, weight loss, and biocompatibility. The results showed that the addition of CQ‐PCL NPs into the scaffolds did not dramatically alter the ultrastructure and properties of the scaffolds, compared to CS/Col/HA scaffolds alone. However, incorporation of CQ‐PCL NPs in the scaffolds improved the release profile of CQ by preventing the initial burst release and prolonging the release rate of CQ. In addition, the CQ‐PCL NPs‐loaded CS/Col/HA scaffolds supported the attachment and proliferation of MC3T3‐E1 osteoblast cells. [ABSTRACT FROM AUTHOR]

In this work, pH-sensitive hydrogel beads based on fish scale collagen and carrageenan were used as a novel allopurinol drug loading system to improve the bioavailability of allopurinol, which is used to treat gout and high levels of uric acid in the human body. The effectiveness of the carrageenan/collagen/allopurinol hydrogel beads in improving the physical properties of allopurinol and the ability for drug release control in different simulated body fluids were evaluated by infrared (IR) spectroscopy, field emission scanning electron microscopy (FESEM), differential scanning calorimetry (DSC), dynamic light scattering (DLS) and Ultraviolet–Vis (UV–Vis) spectroscopy. In addition, the ability of hydrogen bond formation between allopurinol, carrageenan and collagen was calculated theoretically based on the B3LYP/6-31+g(d)//B3LYP/6-311++g(d,p) level of theory. Both the theoretical and experimental results proved that the hydrogen bonds of the functional groups in allopurinol with the functional groups in carrageenan and fish scale collagen contributed to the enhancement of drug release control as well as to the bioavailability of allopurinol loaded into the carrageenan/collagen hydrogel beads. The dissolution of carrageenan/collagen/allopurinol hydrogel beads in different simulated body fluids increased by 1.6 to 6.7 times compared to that of crystalline allopurinol. [ABSTRACT FROM AUTHOR]

Background: The advantages of biological skin dressings like collagen are well-known. It makes wound impermeable to bacteria and creates the most physiological interface between the wound surface and the environment. Silver-sulfadiazine-impregnated collagen (SIC) is a type 1 collagen impregnated with silver sulfadiazine (SSD)-loaded alginate microspheres to deliver SSD in a controlled fashion to manage infected burn wounds for an extended period of time with lesser dressing changes. Materials and Methods: In this study, we used SIC for the treatment of second-degree burn wounds in 25 patients and compared with similar burn wounds in 25 patients treated with conventional dressings. Results: For SIC-treated group, we observed improved wound healing in all the patients after 7 days except two patients who required skin grafting, and none of them had any serious complications. For conventionally treated group, improved wound healing was seen in 14 patients, whereas the rest of the patients required prolong dressing or skin grafting. All the patients who were treated with SIC were satisfied with healing of wound and pain relief. Conclusion: Second-degree burn wounds are well-treated with SIC in the form of good healing, control of infection, and reducing pain without any serious complications when compared with conventional dressing. [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HAc)–hydroxyapatite (HAp) composite hydrogels were developed to improve the biostability and bioactivity of HAc for dermal filler applications. Two kinds of HAc-HAp composite fillers were generated: HAcmicroHAp and HAc-nanoHAp composites. HAc-microHAp was fabricated by mixing HAp microspheres with HAc hydrogels, and HAc-nanoHAp was made by in situ precipitation of nano-sized HAp particles in HAc hydrogels. Emphasis was placed on the effect of HAp on the durability and bioactivity of the fillers. Compared with the pure HAc filler, all of the HAc-HAp composite fillers exhibited significant improvements in volumetric maintenance based on in vivo tests owing to their reduced water content and higher degree of biointegration between the filler and surrounding tissues. HAc-HAp composite fillers also showed noticeable enhancement in dermis recovery, promoting collagen and elastic fiber formation. Based on their long-lasting durability and bioactivity, HAc-HAp composite fillers have great potential for soft tissue augmentation with multifunctionality. [ABSTRACT FROM AUTHOR]

There has been considerable focus in investigations on the delivery systems and clinical applications of bone morphogenetic protein-2 (BMP-2) for novel bone formation. However, current delivery systems require high levels of BMP-2 to exert a biological function. There are several concerns in using of high levels of BMP-2, including safety and the high cost of treatment. Therefore, the development of strategies to decrease the levels of BMP-2 required in these delivery systems is required. In our previous studies, a controlled-release system was developed, which used Traut's reagent and the cross-linker, 4-(N-maleimi-domethyl) cyclohexane-1-carboxylic acid 3-sulfo-N-hydroxysuccinimide ester sodium salt (Sulfo-SMCC), to chemically conjugate BMP-2 directly on collagen discs. In the current study, retention efficiency and release kinetics of stromal cell-derived factor-1α (SDF-1α) cross-linked on collagen scaffolds were detected. In addition, the osteogenic activity of SDF-1α and suboptimal doses of BMP-2 cross-linked on collagen discs following subcutaneous implantation in rats were evaluated. Independent two-tailed t-tests and one-way analysis of variance were used for analysis. In the present study, the controlled release of SDF-1α chemically conjugated on collagen scaffolds was demonstrated. By optimizing the concentrations of Traut's reagent and the Sulfo-SMCC cross-linker, a significantly higher level of SDF-1α was covalently retained on the collagen scaffold, compared with that retained using a physical adsorption method. Mesenchymal stem cell homing indicated that the biological function of the SDF-1α cross-linked on the collagen scaffolds remained intact. In rats, co-treatment with SDF-1α and a suboptimal dose of BMP-2 cross-linked on collagen scaffolds using this chemically conjugated method induced higher levels of ectopic bone formation, compared with the physical adsorption method. No ectopic bone formation was observed following treatment with a suboptimal dose of BMP-2 alone. Therefore, the co-delivery of SDF-1α and a suboptimal dose of BMP-2 chemically conjugated on collagen scaffolds for the treatment of bone injuries reduced the level of BMP-2 required, reducing the risks of side effects. [ABSTRACT FROM AUTHOR]

Several studies have shown the influence of the physical properties of scaffolds on their mechanical properties. An initial characterization of a type of collagen protein was carried out by studying its composition andits solubility at different pH values and infrared spectroscopy. Subsequently, porosity and scaffold pore size were studied, assessing how varying the composition of the initial solution (increasing the protein concentration or adding glutaraldehyde) changed the properties of the final scaffolds obtained. Lastly, rheological measurements were performed to evaluate the mechanical strength of the scaffolds. The initial characterization revealed that the type I collagen protein used is considerably denatured. In addition, increasing the protein content in the scaffold decreases the porosity, related to an increase in the elastic modulus producing an enhancement of its mechanical strength, while adding glutaraldehyde to the scaffold increases its mechanical strength without lowering its pore size or porosity. The results obtained are useful in that they demonstrate that it is possible to design a scaffold with specific properties, by just controlling the collagen concentration or adding glutaraldehyde to the initial solution. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1462-1468, 2016. [ABSTRACT FROM AUTHOR]

Biodegradable hollow capsules filled with fluorescently labelled bovine serum albumin (BSA) as a model drug were prepared via layer-by-layer (LbL) self-assembly of type-I collagen (COL) and hyaluronic acid (HA) using calcium carbonate micro-particles and co-precipitation method. Capsules loaded with fluorescein isothiocyanate (FITC)-BSA, tetramethylrhodamin isothiocyanate (TRITC)-BSA or Alex-Fluor-488-BSA, respectively, were characterised before and after core removal using Confocal Laser Scanning Microscopy (CLSM), whilst the morphologies of individual hollow capsules were assessed using Atomic Force Microscopy (AFM). The sustained release of the encapsulated FITC-BSA protein was attained using enzymatic degradation of the capsule shells by collagenase. The released profile of the fluorescently-labelled BSA indicated that it could be successfully controlled by modulating the number of layers and/or by collagen crosslinking either before or after the capsule's assembly. [ABSTRACT FROM AUTHOR]

Collagen-elastin (CE) scaffolds are frequently used for dermal replacement in the treatment of full-thickness skin defects such as burn wounds. But little is known about the optimal pore size and level of cross-linking. Different formulations of dermal substitutes with unidirectional pores were tested in porcine full-thickness wounds in combination with autologous split skin mesh grafts (SSG). Effect on wound healing was evaluated both macro- and microscopically. CE scaffolds with a pore size of 80 or 100 μm resulted in good wound healing after one-stage grafting. Application of scaffolds with a larger average pore size (120 μm) resulted in more myofibroblasts and more foreign body giant cells (FBGC). Moderate crosslinking impaired wound healing as it resulted in more wound contraction, more FBGC and increased epidermal thickness compared to no cross-linking. In addition, take rate and redness were negatively affected compared to SSG only. Vascularization and the number of myofibroblasts were not affected by cross-linking. Surprisingly, stability of cross-linked scaffolds was not increased in the wound environment, in contrast to in vitro results. Cross-linking reduced the proliferation of fibroblasts in vitro, which might explain the reduced clinical outcome. The non-cross-linked CE substitute with unidirectional pores allowed one-stage grafting of SSG, resulting in good wound healing. In addition, only a very mild foreign body reaction was observed. Cross-linking of CE scaffolds negatively affected wound healing on several important parameters. The optimal non-cross-linked CE substitute is a promising candidate for future clinical evaluation. [ABSTRACT FROM AUTHOR]

Stem cell therapy is well proposed as a potential method for the improvement of neurodegenerative damage in the brain. Among several different procedures to reach the cells into the injured lesion, the intravenous (IV) injection has benefit as a minimally invasive approach. However, for the brain disease, prompt development of the effective treatment way of cellular biodistribution of stem cells into the brain after IV injection is needed. Atelocollagen has been used as an adjunctive material in a gene, drug and cell delivery system because of its extremely low antigenicity and bioabsorbability to protect these transplants from intrabody environment. However, there is little work about the direct effect of atelocollagen on stem cells, we examined the functional change of survival, proliferation, migration and differentiation of cultured neural stem cells (NSCs) induced by atelocollagen in vitro. By 72-h treatment 0.01-0.05 % atelocollagen showed no significant effects on survival, proliferation and migration of NSCs, while 0.03-0.05 % atelocollagen induced significant reduction of neuronal differentiation and increase of astrocytic differentiation. Furthermore, IV treated NSCs complexed with atelocollagen (0.02 %) could effectively migrate into the brain rather than NSC treated alone using chronic alcohol binge model rat. These experiments suggested that high dose of atelocollagen exerts direct influence on NSC function but under 0.03 % of atelocollagen induces beneficial effect on regenerative approach of IV administration of NSCs for CNS disease. [ABSTRACT FROM AUTHOR]

Mechanical properties of collagen films are less than ideal for biomaterial development towards musculoskeletal repair or cardiovascular applications. Herein, we present a collagen-cellulose composite film (CCCF) compared against swine small intestine submucosa in regards to mechanical properties, cell growth, and histological analysis. CCCF was additionally characterized by FE-SEM, NMR, mass spectrometry, and Raman Microscopy to elucidate its physical structure, collagen-cellulose composition, and structure activity relationships. Mechanical properties of the CCCF were tested in both wet and dry environments, with anisotropic stress-strain curves that mimicked soft-tissue. Mesenchymal stem cells, human umbilical vein endothelial cells, and human coronary artery smooth muscle cells were able to proliferate on the collagen films with specific cell orientation. Mesenchymal stem cells had a higher proliferation index and were able to infiltrate CCCF to a higher degree than small intestine submucosa. With the underlying biological properties, we present a collagen-cellulose composite film towards forthcoming biomaterial-related applications. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Controlling cell organization is important in tissue engineering. Guidance by aligned features on scaffolds or stimulation by physical signals can be used to induce cell alignment. We have previously demonstrated a preferred alignment of human MSCs (hMSCs) along the compression loading axis in 3D collagen construct. In this study, we aim to investigate the collagen concentration dependence of the compression-induced hMSC organization. Results demonstrated that the compression-induced alignment and elongation of hMSCs exhibited a biphasic dose-dependent relationship with collagen concentration, and associated well with both collagen ligand density and elastic modulus of the constructs. Moreover, collagen concentration and compression loading significantly affected the expression level of integrin beta 1 and antibody neutralization against this molecule aborted the compression-induced alignment and elongation responses. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. [ABSTRACT FROM AUTHOR]

Type-I collagen is an attractive scaffold material for tissue engineering due to its ability to self-assemble into a fibrillar hydrogel, its innate support of tissue cells through bioactive adhesion sites, and its biodegradability. However, a lack of control of material properties has hampered its utility as a scaffold. We have modified collagen via the addition of methacrylate groups to create collagen methacrylamide (CMA) using a synthesis reaction that allows retention of fundamental characteristics of native collagen, including spontaneous fibrillar self-assembly and enzymatic biodegradability. This method allows for a rapid, five-fold increase in storage modulus upon irradiation with 365 nm light. Fibrillar diameter of CMA was not significantly different from native collagen. Collagenolytic degradability of uncrosslinked CMA was minimally reduced, while photocrosslinked CMA was significantly more resistant to degradation. Live/Dead staining demonstrated that a large majority (71%) of encapsulated mesenchymal stem cells remained viable 24 h after photocrosslinking, which further increased to 81% after 72 h. This material represents a novel platform for creating mechanically heterogeneous environments. [ABSTRACT FROM AUTHOR]

In recent years, electrospinning has increased in popularity as a processing technique for obtaining nanometer-to-micron diameter polymer fibers collected to form a nonwoven scaffold. It possesses the ability to process collagen into nanofibrous scaffolds which have been used for a number of applications, such as artificial vascular grafts and for wound repair. This paper offers a review of some of the basic yet essential aspects of producing nanofibrous scaffolds of collagen by electrospinning. A primer to collagen structure, cross-linking techniques, and electrospinning principles is provided, along with some of the many applications of these unique materials. [ABSTRACT FROM AUTHOR]

Background: Tissue adhesives are useful means for various medical procedures. Since varying requirements cause that a single adhesive cannot meet all needs, bond strength testing remains one of the key applications used to screen for new products and study the influence of experimental variables. This study was conducted to develop an easy to use method to screen and evaluate tissue adhesives for tissue engineering applications. Method: Tissue grips were designed to facilitate the reproducible production of substrate tissue and adhesive strength measurements in universal testing machines. Porcine femoral condyles were used to generate osteochondral test tissue cylinders (substrates) of different shapes. Viability of substrates was tested using PI/FDA staining. Self-bonding properties were determined to examine reusability of substrates (n = 3). Serial measurements (n = 5) in different operation modes (OM) were performed to analyze the bonding strength of tissue adhesives in bone(OM-1) and cartilage tissue either in isolation (OM-2) or under specific requirements in joint repair such as filling cartilage defects with clinical applied fibrin/PLGA-cell-transplants (OM-3) or tissues (OM-4). The efficiency of the method was determined on the basis of adhesive properties of fibrin glue for different assembly times (30 s, 60 s). Seven randomly generated collagen formulations were analyzed to examine the potential of method to identify new tissue adhesives. Results: Viability analysis of test tissue cylinders revealed vital cells (>80%) in cartilage components even 48 h postpreparation. Reuse (n = 10) of test substrate did not significantly change adhesive characteristics. Adhesive strength of fibrin varied in different test settings (OM-1: 7.1 kPa, OM-2: 2.6 kPa, OM-3: 32.7 kPa, OM-4: 30.1 kPa) and was increasing with assembly time on average (2.4-fold). The screening of the different collagen formulations revealed a substance with significant higher adhesive strength on cartilage (14.8 kPa) and bone tissue (11.8 kPa) compared to fibrin and also considerable adhesive properties when filling defects with cartilage tissue (23.2 kPa). Conclusion: The method confirmed adhesive properties of fibrin and demonstrated the dependence of adhesive properties and applied settings. Furthermore the method was suitable to screen for potential adhesives and to identify a promising candidate for cartilage and bone applications. The method can offer simple, replicable and efficient evaluation of adhesive properties in ex vivo specimens and may be a useful supplement to existing methods in clinical relevant settings. [ABSTRACT FROM AUTHOR]

Toxic epidermal necrolysis (TEN) is associated with a significant mortality of 30-50% and longterm sequelae. Treatment includes early admission to a burn unit, where management with precise fluid, electrolyte, protein, and energy supplementation, moderate mechanical ventilation, and expert wound care can be provided. Specific treatment with immunosuppressive drugs or immunoglobulins did not show an improved outcome in most studies and remains controversial. We have treated the cutaneous lesions of seven patients of TEN with collagen sheet dressings and have found a significant reduction in morbidity. The sheets are a one-time dressing, easy to apply and they reduce fluid loss, prevent infection, reduce pain, avoid repeated dressings and gradually peal off as the underlying lesions heal. [ABSTRACT FROM AUTHOR]

Objective: Biological dressings like collagen are impermeable to bacteria, and create the most physiological interface between the wound surface and the environment. Collagen dressings have other advantages over conventional dressings in terms of ease of application and being natural, non-immunogenic, non-pyrogenic, hypo-allergenic, and pain-free. This study aims to compare the efficacy of collagen dressing in treating burn and chronic wounds with that of conventional dressing materials. Materials and Methods: The records of 120 patients with chronic wounds of varied aetiologies and with mean age 43.7 years were collected and analyzed. The patients had been treated either with collagen or other conventional dressing materials including silver sulfadiazine, nadifloxacin, povidone iodine, or honey (traditional dressing material). Patients with co-morbidities that could grossly affect the wound healing like uncontrolled diabetes mellitus, chronic liver or renal disease, or major nutritional deprivation were not included. For the purpose of comparison the patients were divided into two groups; 'Collagen group' and 'Conventional group', each having 60 patients. For assessment the wound characteristics (size, edge, floor, slough, granulation tissue, and wound swab or pus culture sensitivity results) were recorded. With start of treatment, appearance of granulation tissue, completeness of healing, need for skin grafting, and patients' satisfaction was noted for each patient in both groups. Results: With two weeks of treatment, 60% of the 'collagen group' wounds and only 42% of the 'conventional group' wounds were sterile (P=0.03). Healthy granulation tissue appeared earlier over collagen-dressed wounds than over conventionally treated wounds (P=0.03). After eight weeks, 52 (87%) of 'collagen group' wounds and 48 (80%) of 'conventional group' wounds were >75% healed (P=0.21). Eight patients in the 'collagen group' and 12 in the 'conventional group' needed partial split-skin grafting (P=0.04). Collagen-treated patients enjoyed early and more subjective mobility. Conclusion: No significant better results in terms of completeness of healing of burn and chronic wounds between collagen dressing and conventional dressing were found. Collagen dressing, however, may avoid the need of skin grafting, and provides additional advantage of patients' compliance and comfort. [ABSTRACT FROM AUTHOR]

Cartilage extracellular matrix (ECM) is composed primarily of type II collagen (COL II) and large, networks of proteoglycans (PGs) that contain glycosaminoglycans such as hyaluronic acid (HA) and chondroitin sulfate (CS). Since cartilage shows little tendency for self-repair, injuries are kept unhealed for years and can eventually lead to further degeneration. During the past decades, many investigations have pursued techniques to stimulate articular cartilage repair or regeneration. The current study assessed the effects of exogenous glycosaminoglycans (GAGs) including CS-A, CS-B, CS-C, heparan sulfate and HA, administration on human chondrocytes in terms of proliferation and matrix synthesis, while the cells were seeded and grown on the genipin-crosslinked collagen type II (COL II) scaffold. DNA content was measured by Hoechst dye intercalation, matrix deposition was evaluated by DMMB dye. Expression of collagen II and aggrecan mRNAs was assessed by RT-PCR, followed by gel electrophoresis. In a 28-day in vitro culture, administration of 5 μg/ml CS-A, 50 μg/ml CS-B, 50 μg/ml CS-C, 5 μg/ml HS, and 500 kDa HA led to significant increase in biosynthesis rate of PGs. Gene expression of aggrecan and collagen II were upregulated by CS-A, CS-C and HA. These results showed considerable relevance of GAGs to the issue of in vitro/ex vivo neo-cartilage synthesis for tissue engineering and regenerative medical applications. [ABSTRACT FROM AUTHOR]

There is increasing evidence showing that adult stem cells are useful for tissue regeneration. Bone marrow mesenchymal stem cells (MSCs) are self-renewing and are potent in differentiating into multiple cells and tissues. To investigate the practicability of repairing burn wounds with tissue-engineered (TE) skin combined with bone MSCs, we established a burn wound model in the porcine skin. With a controlling temperature and time of the burning device to obtain different degrees of burn wounds, a deep dermal partial thickness burn was introduced to the porcine skin using a heated-brass contact injury at 100°C for 20 s. Collagen-GAG scaffolds were utilized as the matrix; MSCs separated from pigs were seeded on them to form the skin equivalent. When grafted to the burn wounds, the TE skin containing MSCs showed better healing and keratinization, less wound contraction, and more vascularization. Grafts proliferated well and contributed to the neo-tissues. These data suggest that TE skin containing MSCs in a burn defect can accelerate wound healing and receive satisfactory effects. [ABSTRACT FROM AUTHOR]

Studies have shown that exogenous platelet-derived growth factor-BB (PDGF-BB) could accelerate the ulcer healing, but the lack of efficient growth factor delivery system limits its clinical application. Our previous work has demonstrated that the native human PDGF-BB was added a collagen-binding domain (CBD), TKKTLRT, to develop a collagen-based PDGF targeting delivery system. Here, we showed that this CBD-fused PDGF-BB (CBD-PDGF) could bind to collagen membrane efficiently. We used the rabbit dermal ischemic ulcer model to study the effects of CBD-PDGF loaded on collagen membranes. Results revealed that this system maintained a higher concentration and stronger bioactivity of PDGF-BB on the collagen membranes and promoted the re-epithelialization of dermal ulcer wounds, the collagen deposition, and the formation of capillary lumens within the newly formed tissue area. It demonstrated that collagen membranes loaded with collagen-targeting human PDGF-BB could effectively promote ulcer healing. [ABSTRACT FROM AUTHOR]

Background: Peritoneal defects lead to serious postoperative problems. Thus the development of physiological material to cover peritoneal defects is very desirable. Aim: The aim of this study was to develop a transplantable artificial peritoneum. Method: The artificial peritoneum consisted of collagen gel, fibroblasts, and mesothelial cells, and histological features were analyzed. The artificial peritoneum at the site of a peritoneal defect in the rat was transplanted to the abdominal wall. Results: Histological examination revealed that the artificial peritoneum consisted of a flat mesothelial monolayer upon a stromal matrix. All transplanted artificial peritoneums adapted well to the host and prevented severe adhesion. Conclusion: Our artificial peritoneum may be a useful transplantable bioengineered material for repair of surgical peritoneal defects. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We made an artificial skin comprised of a stratified layer of keratinocytes and a dermal matrix with a type I collagen containing fibroblasts. In this work, we showed keratinocyte behavior under primary culture, gel contractions varying with concentration of collagen solution, and cell growth plots in the collagen gel. The optimum behavior of dermal equivalent could be obtained using 3.0 mg/ml collagen solution and attached gel culture. The attached gel culture had a jumping effect of growth factor on cell growth at the lag phase. To develop the artificial skin, 1× 105 cells/cm2 of keratinocytes were cultured on the dermal equivalent at air-liquid interface. Finally, to overcome the problem that artificial skin of collagen gel was torn easily during suturing of grafting, we prepared histocompatible collagen mesh and attached the mesh to the bottom of the gel. Cultured artificial skins were successfully grafted onto rats. [ABSTRACT FROM AUTHOR]