Exploring the Tumor-Associated Risk of Mesenchymal Stem Cell Therapy in Veterinary Medicine.

Mesenchymal stem cell (MSC) therapy has been actively applied in veterinary regenerative medicine to treat various canine and feline diseases. With increasing emphasis on safe cell-based therapies, evaluations of their tumorigenic potential are in great demand. However, a direct confirmation of whether tumors originate from stem cells or host cells is not easily achievable. Additionally, previous studies evaluating injections of high doses of MSCs into nude mice did not demonstrate tumor formation. Recent research focused on optimizing MSC-based therapies for veterinary patients, such as MSC-derived extracellular vesicles in treating different diseases. This progress also signifies a broader shift towards personalized veterinary medicine, where treatments can be tailored to individual pets based on their unique genetic profiles. These findings related to different treatments using MSCs emphasize their future potential for veterinary clinical applications. In summary, because of lower tumor-associated risk of MSCs as compared to embryonic and induced pluripotent stem cells, MSCs are considered a suitable source for treating various canine and feline diseases.

Exceptional Repositioning of Dog Dewormer: Fenbendazole Fever.

Fenbendazole (FZ) is a benzimidazole carbamate drug with broad-spectrum antiparasitic activity in humans and animals. The mechanism of action of FZ is associated with microtubular polymerization inhibition and glucose uptake blockade resulting in reduced glycogen stores and decreased ATP formation in the adult stages of susceptible parasites. A completely cured case of lung cancer became known globally and greatly influenced the cancer community in South Korea. Desperate Korean patients with cancer began self-administering FZ without their physician's knowledge, which interfered with the outcome of the cancer treatment planned by their oncologists. On the basis of presented evidence, this review provides valuable information from PubMed, Naver, Google Scholar, and Social Network Services (SNS) on the effects of FZ in a broad range of preclinical studies on cancer. In addition, we suggest investigating the self-administration of products, including supplements, herbs, or bioactive compounds, by patients to circumvent waiting for long and costly FZ clinical trials.

Superior therapeutic activity of TGF-ß-induced extracellular vesicles against interstitial cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by incapacitating pelvic pain. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are considered key mediators of the paracrine action of MSCs and show better biological activities than the parent MSCs, especially in the bladder tissue, which may be unfavorable for MSC survival. Here, we produced MSC-EVs using advanced three-dimensional (a3D) culture with exogenous transforming growth factor-ß3 (TGF-ß3) (T-a3D-EVs). Treatment with T-a3D-EVs led to significantly enhanced wound healing and anti-inflammatory capacities. Moreover, submucosal layer injection of T-a3D-EVs in chronic IC/BPS animal model resulted in restoration of bladder function, superior anti-inflammatory activity, and recovery of damaged urothelium compared to MSCs. Interestingly, we detected increased TGF-ß1 level in T-a3D-EVs, which might be involved in the anti-inflammatory activity of these EVs. Taken together, we demonstrate the excellent immune-modulatory and regenerative abilities of T-a3D-EVs as observed by recovery from urothelial denudation and dysfunction, which could be a promising therapeutic strategy for IC/BPS.

Double Repositioning: Veterinary Antiparasitic to Human Anticancer.

Drug repositioning, the approach of discovering different uses for existing drugs, has gained enormous popularity in recent years in the anticancer drug discovery field due to the increasing demand for anticancer drugs. Additionally, the repurposing of veterinary antiparasitic drugs for the treatment of cancer is gaining traction, as supported by existing literature. A prominent example is the proposal to implement the use of veterinary antiparasitics such as benzimidazole carbamates and halogenated salicylanilides as novel anticancer drugs. These agents have revealed pronounced anti-tumor activities and gained special attention for "double repositioning", as they are repurposed for different species and diseases simultaneously, acting via different mechanisms depending on their target. As anticancer agents, these compounds employ several mechanisms, including the inhibition of oncogenic signal transduction pathways of mitochondrial respiration and the inhibition of cellular stress responses. In this review, we summarize and provide valuable information about the experimental, preclinical, and clinical trials of veterinary antiparasitic drugs available for the treatment of various cancers in humans. This review suggests the possibility of new treatment options that could improve the quality of life and outcomes for cancer patients in comparison to the currently used treatments.

Effects of carrier solutions on the viability and efficacy of canine adipose-derived mesenchymal stem cells.

BACKGROUND: Mesenchymal stem cells (MSCs) have favorable characteristics that render them a potent therapeutic tool. We tested the characteristics of MSCs after temporal storage in various carrier solutions, such as 0.9% saline (saline), 5% dextrose solution (DS), heparin in saline, and Hartmann's solution, all of which are approved by the U.S. Food and Drug Administration (FDA). Phosphate-buffered saline, which does not have FDA approval, was also used as a carrier solution. We aimed to examine the effects of these solutions on the viability and characteristics of MSCs to evaluate their suitability and efficacy for the storage of canine adipose-derived MSCs (cADMSCs). RESULTS: We stored the cADMSCs in the test carrier solutions in a time-dependent manner (1, 6, and 12 h) at 4 °C, and analyzed cell confluency, viability, proliferation, self-renewability, and chondrogenic differentiation. Cell confluency was significantly higher in 5% DS and lower in phosphate-buffered saline at 12 h compared to other solutions. cADMSCs stored in saline for 12 h showed the highest viability rate. However, at 12 h, the proliferation rate of cADMSCs was significantly higher after storage in 5% DS and significantly lower after storage in saline, compared to the other solutions. cADMSCs stored in heparin in saline showed superior chondrogenic capacities at 12 h compared to other carrier solutions. The expression levels of the stemness markers, Nanog and Sox2, as well as those of the MSC surface markers, CD90 and CD105, were also affected over time. CONCLUSION: Our results suggest that MSCs should be stored in saline, 5% DS, heparin in saline, or Hartmann's solution at 4 °C, all of which have FDA approval (preferable storage conditions: less than 6 h and no longer than 12 h), rather than storing them in phosphate-buffered saline to ensure high viability and efficacy.

Ginseng Gintonin Contains Ligands for GPR40 and GPR55.

Gintonin, a novel ginseng-derived glycolipoprotein complex, has an exogenous ligand for lysophosphatidic acid (LPA) receptors. However, recent lipid analysis of gintonin has shown that gintonin also contains other bioactive lipids besides LPAs, including linoleic acid and lysophosphatidylinositol (LPI). Linoleic acid, a free fatty acid, and LPI are known as ligands for the G-protein coupled receptors (GPCR), GPR40, and GPR55, respectively. We, herein, investigated whether gintonin could serve as a ligand for GPR40 and GPR55, using the insulin-secreting beta cell-derived cell line INS-1 and the human prostate cancer cell line PC-3, respectively. Gintonin dose-dependently enhanced insulin secretion from INS-1 cells. Gintonin-stimulated insulin secretion was partially inhibited by a GPR40 receptor antagonist but not an LPA1/3 receptor antagonist and was down-regulated by small interfering RNA (siRNA) against GPR40. Gintonin dose-dependently induced [Ca2+]i transients and Ca2+-dependent cell migration in PC-3 cells. Gintonin actions in PC-3 cells were attenuated by pretreatment with a GPR55 antagonist and an LPA1/3 receptor antagonist or by down-regulating GPR55 with siRNA. Taken together, these results demonstrated that gintonin-mediated insulin secretion by INS-1 cells and PC-3 cell migration were regulated by the respective activation of GPR40 and GPR55 receptors. These findings indicated that gintonin could function as a ligand for both receptors. Finally, we demonstrated that gintonin contained two more GPCR ligands, in addition to that for LPA receptors. Gintonin, with its multiple GPCR ligands, might provide the molecular basis for the multiple pharmacological actions of ginseng.

Locating the Instant Center of Rotation in the Subaxial Cervical Spine with Biplanar Fluoroscopy during In Vivo Dynamic Flexion-Extension.

BACKGROUND: Recently, biplanar fluoroscopy is used to evaluate the cervical kinematics, especially to locate the instant center of rotation (ICR) during in vivo motion. This study aims to ascertain the ICR at each cervical segment in the sagittal plane during dynamic motion and assess the differences from previous studies. METHODS: While three healthy subjects were performing full flexion-extension, two oblique views aligned horizontally and angled at approximately 55° were obtained by biplanar fluoroscopy. The minimum degree to detect significant movement in a helical axis model was set at 2°, and anterior-posterior and superior-inferior locations of each ICR were defined. To evaluate the possible distribution area and overlapping area of the ICR with disc space, we drew a circle by using the calculated distance between each coordination and the mean coordination of ICR as the radius. RESULTS: During flexion-extension motion, the mean superior-inferior location of the ICR became progressively more superior, except the C5-6 segment (p = 0.015), and the mean anterior-posterior location of the ICR became progressively more anterior without exception from C2-3 to C6-7 segments, but anterior-posterior ICR locations were not significantly different among segments. The overlapping area with the distribution circle of ICR was mainly located in the posterior half in the C3-4 segment, but the overlapping area was about 80% of the total disc space in C4-5 and C6-7 segments. The overlapping was more noticeable in the lower cervical segments after exclusion of the outlier data of the C5-6 segment in subject 1. CONCLUSIONS: The ICR in the cervical spine showed a trend of moving progressively more superiorly and anteriorly and the disc space overlapping the distribution circle of ICR increased along the lower motion segments except the C5-6 segment. These findings could provide a good basis for level-specific cervical arthroplasty designs.

Translational assessment of a genetic engineering methodology to improve islet function for transplantation.

BACKGROUND: The functional quality of insulin-secreting islet beta cells is a major factor determining the outcome of clinical transplantations for diabetes. It is therefore of importance to develop methodological strategies aiming at optimizing islet cell function prior to transplantation. In this study we propose a synthetic biology approach to genetically engineer cellular signalling pathways in islet cells. METHODS: We established a novel procedure to modify islet beta cell function by combining adenovirus-mediated transduction with reaggregation of islet cells into pseudoislets. As a proof-of-concept for the genetic engineering of islets prior to transplantation, this methodology was applied to increase the expression of the V1b receptor specifically in insulin-secreting beta cells. The functional outcomes were assessed in vitro and in vivo following transplantation into the anterior chamber of the eye. FINDINGS: Pseudoislets produced from mouse dissociated islet cells displayed basic functions similar to intact native islets in terms of glucose induced intracellular signalling and insulin release, and after transplantation were properly vascularized and contributed to blood glucose homeostasis. The synthetic amplification of the V1b receptor signalling in beta cells successfully modulated pseudoislet function in vitro. Finally, in vivo responses of these pseudoislet grafts to vasopressin allowed evaluation of the potential benefits of this approach in regenerative medicine. INTERPRETATION: These results are promising first steps towards the generation of high-quality islets and suggest synthetic biology as an important tool in future clinical islet transplantations. Moreover, the presented methodology might serve as a useful research strategy to dissect cellular signalling mechanisms of relevance for optimal islet function.

DC-SIGN expression in Hofbauer cells may play an important role in immune tolerance in fetal chorionic villi during the development of preeclampsia.

Immune tolerance at feto-maternal interfaces is a complex phenomenon. Although maternal decidual macrophages are well-known immune cells, little is known about fetal-derived macrophages (Hofbauer cells) within chorionic villi. Preeclampsia (PE) is a major cause of maternal mortality in the field of obstetrics, and the innate immunological role of maternal decidual macrophages is well known. In this study, we assessed the differential phenotypes and marker expression in fetal macrophages, known as dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN)-positive Hofbauer cells. We compared Hofbauer cell properties between normal and PE placenta chorionic villi and performed sequential staining of DC-SIGN, CD14, and CD68 to evaluate the existence of Hofbauer cells. Furthermore, to evaluate the immunological function of these cells, we stained the cells for CD163, a marker of immunoregulatory type 2 (M2) macrophages. Additionally, we examined the expression of the immunosuppressive cytokine interleukin (IL)-10, which is known to be produced by M2 macrophages. DC-SIGN+/CD14+, DC-SIGN+/CD68+, and CD163+/DC-SIGN+ cells were quantified based on photomicrographs. The results showed that CD14, CD163, DC-SIGN, and IL-10 levels were significantly downregulated in PE compared with normal. Additionally, CD163+/DC-SIGN+ Hofbauer cells were significantly less frequent in PE than in normal. DC-SIGN Hofbauer cells produced IL-10 at lower levels in the PE than in the normal. Thus, we speculate that fetal-derived Hofbauer cells may play an important role in normal pregnancy with immunosuppressive effects based on their M2 macrophage characteristics to maintain immune tolerance during pregnancy. Additionally, in PE, these functions were defective, supporting the roles of these macrophages in PE development.

Transplantation of Adipose-Derived Stem Cell Sheet Attenuates Adverse Cardiac Remodeling in Acute Myocardial Infarction.

Adipose-derived stem cell (ADSC) transplantation has been proposed to improve cardiac function and acute myocardial infarction (AMI). Recently, cell sheet technology has been investigated for its potential applicability in cardiac injury. However, a detailed comparison of the functional recovery in the injured myocardium between cell sheets and conventional cell injection has not been adequately examined. ADSCs were isolated from the inguinal fat tissue of ICR mice. Three groups of AMI induction only (sham), intramyocardial injection of ADSCs (imADSC), and ADSC sheet transplantation (shADSC) were compared by using rat AMI models. Engraftment of ADSCs was better sustained through 28 days in the shADSC group compared with the imADSC group. Ejection fraction was improved in both imADSC and shADSC groups compared with the sham group. Ventricular wall thickness in the infarct zone was higher in the shADSC group compared with both imADSC and sham groups. Growth factor and cytokine expression in the implanted heart tissue were higher in the shADSC group compared with both imADSC and sham groups. Furthermore, only the shADSC group showed donor-derived vessels at the peri-infarct zone. Taken together, these results indicate that, although shADSC resulted in a similar improvement in left ventricular systolic function, it significantly promoted cellular engraftment and upregulated growth factor and cytokine expression, and, ultimately, attenuated adverse cardiac remodeling in rat AMI models compared with imADSC.

Repositioning Bevacizumab: A Promising Therapeutic Strategy for Cartilage Regeneration.

Drug discovery and development has been garnering an increasing trend of research due to the growing incidence of the diverse types of diseases. Recently, drug repositioning, also known as drug repurposing, has been emerging parallel to cancer and tissue engineering studies. Drug repositioning involves the application of currently approved or even abandoned drugs as alternative treatments to other diseases or as biomaterials in other fields including cell therapy and tissue engineering. In this review, the advancement of the antiangiogenesis drugs that were used as treatment for cancer and other diseases, with particular focus on bevacizumab, will be described. This will include an overview of the nature and progression of osteoarthritis (OA), one of the leading global degenerative diseases that cause morbidity, and the development of its therapeutic strategies. In addition, this will also feature the nonsteroidal anti-inflammatory drugs that are commonly prescribed for OA and the benefits of repositioning bevacizumab as alternative treatments for other diseases and as biomaterials for cartilage regeneration. To date, a few number of studies, employing different modes of administration and varying dosages in diverse animal models, have shown that bevacizumab can be used as a signal and can promote both in vitro and in vivo cartilage regeneration. However, other antiangiogenesis drugs and their effects in chondrogenesis and cartilage regeneration are also worth investigating.

Ectopic overexpression of Nanog induces tumorigenesis in non-tumorous fibroblasts.

Key regulatory genes in pluripotent stem cells are of interest not only as reprogramming factors but also as regulators driving tumorigenesis. Nanog is a transcription factor involved in the maintenance of embryonic stem cells and is one of the reprogramming factors along with Oct4, Sox2, and Lin28. Nanog expression has been detected in different types of tumors, and its expression is a poor prognosis for cancer patients. However, there is no clear evidence that Nanog is functionally involved in tumorigenesis. In this study, we induced overexpression of Nanog in mouse embryonic fibroblast cells and subsequently assessed their morphological changes, proliferation rate, and tumor formation ability. We found that Nanog overexpression induced immortalization of mouse embryonic fibroblast cells (MEFs) and increased their proliferation rate in vitro. We also found that formation of tumors after subcutaneous injection of retroviral-Nanog infected MEFs (N-MEFs) into athymic mouse. Cancer-related genes such as Bmi1 were expressed at high levels in N-MEFs. Hence, our results demonstrate that Nanog is able to transform normal somatic cells into tumor cells.

SIGN-R1 and complement factors are involved in the systemic clearance of radiation-induced apoptotic cells in whole-body irradiated mice.

Although SIGN-R1-mediated complement activation pathway has been shown to enhance the systemic clearance of apoptotic cells, the role of SIGN-R1 in the clearance of radiation-induced apoptotic cells has not been characterized and was investigated in this study. Our data indicated that whole-body γ-irradiation of mice increased caspase-3(+) apoptotic lymphocyte numbers in secondary lymphoid organs. Following γ-irradiation, SIGN-R1 and complements (C4 and C3) were simultaneously increased only in the mice spleen tissue among the assessed tissues. In particular, C3 was exclusively activated in the spleen. The delayed clearance of apoptotic cells was markedly prevalent in the spleen and liver of SIGN-R1 KO mice, followed by a significant increase of CD11b(+) cells. These results indicate that SIGN-R1 and complement factors play an important role in the systemic clearance of radiation-induced apoptotic innate immune cells to maintain tissue homeostasis after γ-irradiation.

Influence of pain sensitivity on surgical outcomes after lumbar spine surgery in patients with lumbar spinal stenosis.

STUDY DESIGN: Prospective observational study. OBJECTIVE: To assess the influence of pain sensitivity on surgical outcomes after lumbar spine surgery in patients with lumbar spinal stenosis (LSS). SUMMARY OF BACKGROUND DATA: No previous study has investigated the relationship between the surgical outcomes for LSS and pain sensitivity questionnaire (PSQ) scores. METHODS: The study included 171 patients who were scheduled to undergo spine surgery for LSS. On the basis of their PSQ scores, patients were assigned to either a low (PSQ score<6.5, n=87) or high PSQ group (PSQ score≥6.5, n=84). The primary outcome was the Oswestry Disability Index (ODI) at 12 months after surgery. RESULTS: The ODI at 12 months after surgery was significantly lower in the low PSQ group than in the high PSQ group. Twelve months after surgery, the mean ODI scores (95% confidence interval) in the low and high PSQ groups were 21.1 (16.8-25.5) and 29.6 (25.0-34.1), respectively. The difference (95% confidence interval) in the ODI between the 2 groups was 3.2 (-14.7 to -2.2) (P=0.009). There were significant differences in the secondary endpoints, including the ODI and visual analogue scale (VAS) scores for back and leg pain, in the follow-up assessments during a 12-month period after surgery, between the 2 groups (PSQ group; P<0.001 for the ODI, VAS score for back pain, and VAS score for leg pain). However, the patterns of changes of the ODI and VAS scores for back pain and leg pain in the follow-up assessments during a 12-month period were not significantly different (interaction between the PSQ group and follow-up assessment time; P=0.757, 0.126, and 0.950, respectively). CONCLUSION: Patients with high pain sensitivity may display less improvement in back pain, leg pain, and disability after surgery for LSS compared with patients with low pain sensitivity. Furthermore, the PSQ can be used to predict surgical outcomes after spine surgery for LSS. LEVEL OF EVIDENCE: 2.

Unexpected angular or rotational deformity after corrective osteotomy.

BACKGROUND: Codman's paradox reveals a misunderstanding of geometry in orthopedic practice. Physicians often encounter situations that cannot be understood intuitively during orthopedic interventions such as corrective osteotomy. Occasionally, unexpected angular or rotational deformity occurs during surgery.This study aimed to draw the attention of orthopedic surgeons toward the concepts of orientation and rotation and demonstrate the potential for unexpected deformity after orthopedic interventions. This study focused on three situations: shoulder arthrodesis, femoral varization derotational osteotomy, and femoral derotation osteotomy. METHODS: First, a shoulder model was generated to calculate unexpected rotational deformity to demonstrate Codman's paradox. Second, femoral varization derotational osteotomy was simulated using a cylinder model. Third, a reconstructed femoral model was used to calculate unexpected angular or rotational deformity during femoral derotation osteotomy. RESULTS: Unexpected external rotation was found after forward elevation and abduction of the shoulder joint. In the varization and derotation model, closed-wedge osteotomy and additional derotation resulted in an unexpected extension and valgus deformity, namely, under-correction of coxa valga. After femoral derotational osteotomy, varization and extension of the distal fragment occurred, although the extension was negligible. CONCLUSIONS: Surgeons should be aware of unexpected angular deformity after surgical procedure involving bony areas. The degree of deformity differs depending on the context of the surgical procedure. However, this study reveals that notable deformities can be expected during orthopedic procedures such as femoral varization derotational osteotomy.

Flexible and transparent gas molecule sensor integrated with sensing and heating graphene layers.

Graphene leading to high surface-to-volume ratio and outstanding conductivity is applied for gas molecule sensing with fully utilizing its unique transparent and flexible functionalities which cannot be expected from solid-state gas sensors. In order to attain a fast response and rapid recovering time, the flexible sensors also require integrated flexible and transparent heaters. Here, large-scale flexible and transparent gas molecule sensor devices, integrated with a graphene sensing channel and a graphene transparent heater for fast recovering operation, are demonstrated. This combined all-graphene device structure enables an overall device optical transmittance that exceeds 90% and reliable sensing performance with a bending strain of less than 1.4%. In particular, it is possible to classify the fast (≈14 s) and slow (≈95 s) response due to sp(2) -carbon bonding and disorders on graphene and the self-integrated graphene heater leads to the rapid recovery (≈11 s) of a 2 cm × 2 cm sized sensor with reproducible sensing cycles, including full recovery steps without significant signal degradation under exposure to NO2 gas.

A physicochemical mechanism of chemical gas sensors using an AC analysis.

Electrical modeling of the chemical gas sensors was successfully applied to TiO2 nanofiber gas sensors by developing an equivalent circuit model where the junction capacitance as well as the resistance can be separated from the comparable stray capacitance. The Schottky junction impedance exhibited a characteristic skewed arc described by a Cole-Davidson function, and the variation of the fit and derived parameters with temperature, bias, and NO2 gas concentration indicated definitely a physicochemical sensing mechanism based on the Pt|TiO2 Schottky junctions against the conventional supposition of the enhanced sensitivity in nanostructured gas sensors with high grain boundary/surface area. Analysis on a model Pt|TiO2|Pt structure also confirmed the characteristic impedance response of TiO2 nanofiber sensors.

Trends in tissue engineering for blood vessels.

Over the years, cardiovascular diseases continue to increase and affect not only human health but also the economic stability worldwide. The advancement in tissue engineering is contributing a lot in dealing with this immediate need of alleviating human health. Blood vessel diseases are considered as major cardiovascular health problems. Although blood vessel transplantation is the most convenient treatment, it has been delimited due to scarcity of donors and the patient's conditions. However, tissue-engineered blood vessels are promising alternatives as mode of treatment for blood vessel defects. The purpose of this paper is to show the importance of the advancement on biofabrication technology for treatment of soft tissue defects particularly for vascular tissues. This will also provide an overview and update on the current status of tissue reconstruction especially from autologous stem cells, scaffolds, and scaffold-free cellular transplantable constructs. The discussion of this paper will be focused on the historical view of cardiovascular tissue engineering and stem cell biology. The representative studies featured in this paper are limited within the last decade in order to trace the trend and evolution of techniques for blood vessel tissue engineering.

Human telomerase reverse transcriptase and glucose-regulated protein 78 increase the life span of articular chondrocytes and their repair potential.

BACKGROUND: Like all mammalian cells, normal adult chondrocytes have a limited replicative life span, which decreases with age. To facilitate the therapeutic use of chondrocytes from older donors, a method is needed to prolong their life span. METHODS: We transfected chondrocytes with hTERT or GRP78 and cultured them in a 3-dimensional atelocollagen honeycomb-shaped scaffold with a membrane seal. Then, we measured the amount of nuclear DNA and glycosaminoglycans (GAGs) and the expression level of type II collagen as markers of cell proliferation and extracellular matrix formation, respectively, in these cultures. In addition, we allografted this tissue-engineered cartilage into osteochondral defects in old rabbits to assess their repair activity in vivo. RESULTS: Our results showed different degrees of differentiation in terms of GAG content between chondrocytes from old and young rabbits. Chondrocytes that were cotransfected with hTERT and GRP78 showed higher cellular proliferation and expression of type II collagen than those of nontransfected chondrocytes, regardless of the age of the cartilage donor. In addition, the in vitro growth rates of hTERT- or GRP78-transfected chondrocytes were higher than those of nontransfected chondrocytes, regardless of donor age. In vivo, the tissue-engineered cartilage implants exhibited strong repairing activity, maintained a chondrocyte-specific phenotype, and produced extracellular matrix components. CONCLUSIONS: Focal gene delivery to aged articular chondrocytes exhibited strong repairing activity and may be therapeutically useful for articular cartilage regeneration.