Invasive experimental brain surgery for dementia: Ethical shifts in clinical research practices?

The increasing dementia prevalence worldwide is driving the testing of novel therapeutic approaches, such as invasive brain technologies, despite limited clinical evidence and the risk of accelerating cognitive decline. Our manuscript (a) reviews the NIH Clinicaltrials.gov database for deep brain stimulation, stem cell implantation, and gene therapy trials on people with dementia; (b) discusses issues on beneficence, nonmaleficence, and autonomy associated with these trials; and (c) proposes nine recommendations that build on elements from the Declaration of Helsinki. We found 49 preregistered high-risk trials from nine countries planning to or involving 11,801 people with Alzheimer's or Lewy body dementia or dementia secondary to Parkinson's or Huntington's disease. Most of the people with Alzheimer's who are in these trials are from North America and East Asia. There is substantial heterogeneity in the enrolment criteria, even for trials recruiting only those with Alzheimer's disease. Although most trials enrol people in mild to moderate stages of Alzheimer's disease, trials in China enrol people who have severe Alzheimer's. Our findings highlight a pressing need to review and refine the enrolment criteria for invasive neural trials in people with dementia, considering risks, potential benefits, and capacity for informed consent. As a multidisciplinary team from Australia, the USA, Canada, and Germany with expertise in neurology, neuroscience, and ethics, we examine how it is essential to balance the risks of invasive neural research in a vulnerable population with limited capacity to provide informed consent to help advance the body of knowledge regarding a disease with limited therapeutic options.

Impact of fetal brain tissue derived mesenchymal stem cell and fibrin glue on facial nerve crash injury

Background/aim: To evaluate the clinical and histopathological effects of fetal brain tissue derived mesenchymal stem cells (FBTMSC) and fibrin glue (FG) on the facial nerve (FN) regeneration in rats with traumatic FN injury. Materials and methods: Twenty-eight Sprague Dawley rats were included in the study and divided into 4 groups. Traumatic FN injury (FP) was created by a surgical clamp compression to the main trunk of left FN in all groups. In the control group (group 1) no treatment was applied, in group 2 (FBTMSC group) 2 × 106 FBTMSC was injected, in group 3 (FG group) only FG was applied, in group 4 (FBTMSC and FG groups) both FBTMSC and FG were applied to the injured section of the nerve. The FN functions were evaluated clinically, immediately after the procedure and at 3rd, 5th, and 8th weeks postoperatively. The FNs of all subjects were excised after the 8th week; then the rats were sacrificed. The presence of stem cells in the injured zone was assessed using bromo-deoxyuridine (BrdU), and apoptosis was determined by the TUNEL method. Results: After the damage, total FP was observed in all subjects. Statistically significant functional improvement was observed in group 4 compared to all other groups (P < 0.005). TUNEL-positive cell count was statistically significantly higher in the control group than the other groups (P < 0.001). TUNEL-positive cell count was statistically significantly lower in group 4 than the other groups. The proportion of BrdU-stained cells in group 4 (5%) was higher than group 2 (2%). Conclusion: Clinically and histopathologically FBTMSC applied with FG may play a promising role as a regenerative treatment in posttraumatic FP.

[Efficacy of treatment of lower-limb critical ischaemia by methods of indirect revascularization]. / Éffektivnost' lecheniia kriticheskoi ishemii nizhnikh konechnostei metodami nepriamoi revaskuliarizatsii.

AIM: The study was aimed at comparing the efficacy of implantation of autologous bone marrow cells with that of revascularizing osteotrephination in treatment of lower limb chronic critical ischaemia in patients with a poor distal vascular bed. PATIENTS AND METHOD: We analysed the results of comprehensive examination and treatment of a total of 60 patients presenting with lower limb chronic critical ischaemia due to atherosclerotic lesions of the femoropopliteal-tibial segment. According to the technology of treatment, the patients were divided into two statistically homogenous groups of 30 people each. Group One patients underwent standard revascularizing osteotrephination and Group Two patients in accordance with the original technique received intramuscular implantation of 40 ml of autologous bone marrow cells, with this volume distributed in 2-ml injections to 20 points of the muscles of the crus and femur along the internal and external surface. RESULTS: The use of the original technique of treatment made it possible to achieve the clinical status in the form of moderate or minimal improvement 6 months after bone marrow cells implantation in 29 (96.7%) patients and after 12 months in 28 (93.3%) patients, whereas after revascularizing osteotrephination in 25 (83.3%) and 20 (66.7%) patients, respectively. In the remote period after 12 months, the limb was saved in 28 (93.3%) and 26 (86.7%) patients in Group Two and Group One, respectively. The patients of the second group as compared with those of the first group after 12 months demonstrated a statistically significant increase in the physical health component by 19.8% and the mental health component by 9.8%. CONCLUSION: Implantation of autologous bone-marrow cells in chronic critical limb ischaemia is pathogenetically substantiated and makes it possible to optimize the results of treatment of patients.

Sensorimotor Functional and Structural Networks after Intracerebral Stem Cell Grafts in the Ischemic Mouse Brain.

Past investigations on stem cell-mediated recovery after stroke have limited their focus on the extent and morphological development of the ischemic lesion itself over time or on the integration capacity of the stem cell graft ex vivo However, an assessment of the long-term functional and structural improvement in vivo is essential to reliably quantify the regenerative capacity of cell implantation after stroke. We induced ischemic stroke in nude mice and implanted human neural stem cells (H9 derived) into the ipsilateral cortex in the acute phase. Functional and structural connectivity changes of the sensorimotor network were noninvasively monitored using magnetic resonance imaging for 3 months after stem cell implantation. A sharp decrease of the functional sensorimotor network extended even to the contralateral hemisphere, persisting for the whole 12 weeks of observation. In mice with stem cell implantation, functional networks were stabilized early on, pointing to a paracrine effect as an early supportive mechanism of the graft. This stabilization required the persistent vitality of the stem cells, monitored by bioluminescence imaging. Thus, we also observed deterioration of the early network stabilization upon vitality loss of the graft after a few weeks. Structural connectivity analysis showed fiber-density increases between the cortex and white matter regions occurring predominantly on the ischemic hemisphere. These fiber-density changes were nearly the same for both study groups. This motivated us to hypothesize that the stem cells can influence, via early paracrine effect, the functional networks, while observed structural changes are mainly stimulated by the ischemic event.SIGNIFICANCE STATEMENT In recent years, research on strokes has made a shift away from a focus on immediate ischemic effects and towards an emphasis on the long-range effects of the lesion on the whole brain. Outcome improvements in stem cell therapies also require the understanding of their influence on the whole-brain networks. Here, we have longitudinally and noninvasively monitored the structural and functional network alterations in the mouse model of focal cerebral ischemia. Structural changes of fiber-density increases are stimulated in the endogenous tissue without further modulation by the stem cells, while functional networks are stabilized by the stem cells via a paracrine effect. These results will help decipher the underlying networks of brain plasticity in response to cerebral lesions and offer clues to unravelling the mystery of how stem cells mediate regeneration.

Use of autologous bone marrow stem cell implantation for osteonecrosis of the knee in sickle cell disease: a preliminary report.

BACKGROUND: The purpose of our study was to evaluate safety, feasibility and clinical results of bone marrow mononuclear cell (BMC) implantation for early-stage osteonecrosis of the knee (OK) secondary to sickle cell disease. METHODS: Thirty-three SCD patients (45 knees) with OK treated with BMC implantation in the osteonecrotic lesion were clinically and functionally evaluated through the American Knee Society Clinical Score (KSS), Knee Functional Score (KFS) and Numeric Rating Scale (NRS) pain score. MRI and radiographic examinations of the knee were assessed during a period of five years after intervention. RESULTS: No complications or serious adverse event were associated with BMC implantation. From preoperative assessment to the latest follow-up, there was a significant (p < 0.001) improvement of clinical KSS (64.3 ± 9.7, range: 45-80 and 2.2 ± 4.1, range: 84-100, respectively), KFS (44.5 ± 8.0, range: 30-55 and 91.6 ± 5.8, range: 80-100, respectively) and reduction of NRS pain score (6.7 ± 1.2, range: 4-9 and 3.4 ± 1.0, range: 2-5, respectively). In total, 87% of patients (29/33) consistently experienced improvements in joint function and activity level as compared to preoperative score. No patient had additional surgery following BMC implantation. Radiographic assessment showed joint preservation and no progression to subchondral collapse at most recent follow-up. CONCLUSIONS: The technique of BMC implantation is a promising, relatively simple and safe procedure for OK in SCD patients. Larger and long-term controlled trials are needed to support its clinical effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov NCT02448121 . Retrospectively registered 19 May 2015.

Potential of mesenchymal stem cell in stabilization of abdominal aortic aneurysm sac.

BACKGROUND: In their origin, abdominal aortic aneurysms (AAAs) are related to an inflammatory reaction within the aortic wall, which can lead to weakness and degeneration of this structure. One of the most widely accepted treatment modalities for AAAs is the placement of stent grafts. Nevertheless, in some patients blood re-enters the aneurysm sac, creating so-called leaks, which constitute a renewed risk of rupture and death.This study explores the possibility of filling aneurysm sacs treated by endovascular aneurysm repair with adipose tissue-derived mesenchymal stem cells (ASCs) in a porcine model. METHODS: We developed a porcine model using 22 animals by creating an artificial AAA made with a Dacron patch. AAAs were then treated with a coated stent that isolated the aneurysm sac, after which we introduced allogeneic ASC into the sac. Animals were followed-up for up to 3 mo. The experiment consisted of the aforementioned surgical procedure performed first, followed by computed tomography and echo-Doppler imaging during the follow-up, and finally, after sacrificing the animals, histologic analysis of tissue samples from the site of cell implantation by a blinded observer and the detection of implanted cells by immunofluorescence detection of the Y chromosome. RESULTS: Our findings demonstrate the survival of ASCs over the 3 mo after implantation and histologic changes associated with this treatment. Treated animals had less acute and chronic inflammation throughout the study period, and we observed increasing fibrosis of the aneurysm sac, no accumulation of calcium, and a regeneration of elastic fibers in the artery. CONCLUSIONS: The combination of endovascular aneurysm repair and cell therapy on AAAs has promising results for the stabilization of the sac, resulting in the generation of living tissue that can secure the stent graft and even showing some signs of wall regeneration. The therapeutic value of such cell-based therapy will require further investigation.

Neurosurgical therapy possibilities in treatment of Huntington disease: An update.

INTRODUCTION: Huntington's disease (HD) is a hereditary condition caused by the expansion of the CAG trinucleotide in the huntingtin gene on chromosome 4, resulting in motor, cognitive, and psychiatric disorders that significantly impact patients' quality of life. Despite the lack of effective treatments for the disease, various surgical strategies have been explored to alleviate symptoms and slow its progression. METHODOLOGY: A comprehensive systematic literature review was conducted, including MeSH terms, yielding only 38 articles that were categorized based on the surgical procedure. The study aimed to describe the types of surgeries performed and their efficacy in HD patients. RESULTS: Deep brain stimulation (DBS) involved 41 predominantly male patients with bilateral implantation in the globus pallidus, showing a preoperative Unified Huntington's Disease Rating Scale (UHDRS) score of 60.25 ± 16.13 and a marked postoperative value of 48.54 ± 13.93 with a p < 0.018 at one year and p < 0.040 at three years. Patients experienced improvement in hyperkinesia but worsening of bradykinesia. Additionally, cell transplantation in 119 patients resulted in a lower preoperative UHDRS score of 34.61 ± 14.61 and a significant postoperative difference of 32.93 ± 15.87 (p < 0.016), respectively, in the first to third years of following. Some now, less used procedures were crucial for understanding brain function, such as pallidotomies in 3 patients, showing only a 25 % difference from their baseline. CONCLUSION: Despite advancements in technology, there is still no curative treatment, only palliative options. Promising treatments like trophic factor implantation offer new prospects for the future.

Juvenile Osteochondritis Dissecans: Current Concepts.

Osteochondritis dissecans (OCD) primarily damages the subchondral bone, leading to damage to the articular cartilage. Juvenile OCD (JOCD) of the knee is limited to skeletally immature and young patients with open growth plates on radiographs. We conducted a review of PubMed articles up until March 16, 2024, using a combination of the following keywords: knee, juvenile, and osteochondritis dissecans. This narrative review included a total of 56 relevant articles that investigated the etiology, incidence, clinical presentation, imaging, classification, and treatment of JOCD of the knee in patients less than 20 years of age. The exact etiology is controversial. Most authors believe that the disease involves multiple theories, such as ischemia, recurrent trauma, and genetic predisposition. Radiographs, the first imaging study in this patient group, cannot determine the stability or instability of the surface cartilage of the OCD lesion. As a result, MRI has become a recommended diagnostic method for determining OCD stability and providing important information for determining a treatment plan. For stable JOCD lesions, nonsurgical treatment is often advised. For unstable and stable lesions that do not respond to nonsurgical treatment, several surgical techniques with good healing rates are available.

Efficacy of autologous stem cell therapy in femoral head avascular necrosis: a comparative study.

OBJECTIVE: Avascular necrosis of the femoral head is a disease usually seen in middle-aged individuals. Although many aetiological factors have been blamed, there are still aetiological factors that have not been fully elucidated. Although treatment options show a wide range, early and appropriate treatment is of great importance to preserve the hip joint. In our study, we compared the results of core decompression and core decompression combined with bone marrow mesenchymal stem cell implantation in patients with avascular necrosis of the femoral head. MATERIAL METHOD: In this retrospective study, Steinberg stage 1-2 patients operated on for avascular necrosis of the femoral head between 2018 and 2023 were analysed. Separate groups were formed from patients who underwent isolated core decompression and core decompression + bone marrow mesenchymal stem cell implantation. Age, gender, Steinberg staging, aetiology of the disease, follow-up period, progression to hip arthroplasty, Vas scores, Harris hip scores (HHS), and complications were evaluated. Harris hip scores at preoperative and 2-year follow-up periods; VAS scores at preoperative, 3-month, 6-month, 1-year, and 2-year follow-up periods were analysed. RESULTS: In the study, 44 patients were analysed. While 25 patients underwent core decompression only (group 1), 19 patients underwent core decompression and bone marrow mesenchymal stem cell implantation (group 2). The mean age of the patients in group 1 was 39.3 ± 6.5 years, and the mean age of the patients in group 2 was 38.4 ± 6.7 years. The mean follow-up was 31.85 ± 4.4 months in group 1 and 32.2 ± 4.1 months in group 2. Total hip arthroplasty was performed in 2 of the patients in group 1 (one of the patients underwent total hip arthroplasty at month 28 and the other at month 33). CONCLUSION: The treatment of avascular necrosis of the femoral head varies according to various staging methods. Early diagnosis of the disease and correct treatment are very important for the patient's quality of life in the future. In our research, we found that patients who received both core decompression and stem cell implantation for early-stage avascular necrosis of the femoral head exhibited decreased pain at the 6-month, 1-year, and 2-year follow-up examinations. Additionally, their hip function improved at the 24-month mark according to the HHS evaluation.

In silico evaluation of the mechanical stimulation effect on the regenerative rehabilitation for the articular cartilage local defects.

Osteoarthritis is one of the most severe diseases of the human musculoskeletal system, and therefore, for many years, special attention has been paid to the search for effective methods of its treatment. However, even the most modern methods only in a limited number of cases in the early or intermediate stages of osteoarthritis lead to positive treatment results. In the later stages of development, osteoarthritis is practically incurable and most often ends with disability or the need for joint replacement for a large number of people. One of the main reasons hindering the development of osteoarthritis treatment methods is the peculiarities of articular cartilage, in which there is practically no vascular network and tissue homeostasis is carried out mainly due to the diffusion of nutrients present in the synovial fluid. In modern medicine, for the treatment of osteoarthritis, tissue engineering strategies have been developed based on the implantation of scaffolds populated with chondrogenic cells into the area of the defect. In vitro studies have established that these cells are highly mechanosensitive and, under the influence of mechanical stimuli of a certain type and intensity, their ability to proliferate and chondrogenesis increases. This property can be used to improve the efficiency of regenerative rehabilitation technologies based on the synergistic combination of cellular technologies, tissue engineering strategies, and mechanical tissue stimulation. In this work, using a regenerative rehabilitation mathematical model of local articular cartilage defects, numerical experiments were performed, the results of which indicate that the micro-and macro environment of the restored tissue, which changes during mechanical stimulation, has a significant effect on the formation of the extracellular matrix, and, consequently, cartilage tissue generally. The results obtained can be used to plan strategies for mechanical stimulation, based on the analysis of the results of cell proliferation experimental assessment after each stimulation procedure in vivo.

Brief exposure of neonatal testis cells to EGF or GDNF alters the regenerated tissue.

We have previously shown that implantation of testis cell aggregates under the back skin of immunodeficient mice results in de novo regeneration of testis tissue. We used this unique model to investigate the effects of epidermal growth factor (EGF) and glial cell-derived neurotrophic factor (GDNF) on testis cord development. Neonatal piglet testis cells were briefly (<1 h) exposed to either low (L: 0.02 µg/mL) or high (H: 2 µg/mL) doses of EGF, GDNF, or vehicle (control), before implantation in recipient mice. Randomly selected implants were removed from each mouse at 1, 2, 4, and 8 weeks post-implantation. GDNF-L implants showed increased testis cord development over time, and EGF-L implants had increased cross-sectional area. The ratio of regular cords decreased over time in EGF-H and GDNF-H implants and was replaced by a higher ratio of irregular cords in GDNF-H. EGF-L and GDNF-H implants were quickest to display rete testis-like structures. Overall, the lower dose of each growth factor was more effective than its higher dose in improving the implantation outcomes. This is the first comprehensive assessment of these key growth factors on de novo formation (regeneration) of testis tissue. Lay summary: In recent decades, testicular cancer rates have quadrupled in young men while sperm counts have dropped by half. Both conditions may be related to exposure of fetuses or infants to noxious substances causing disruption of normal testis development. To study the effects of any putative factor on testis development, we established an animal model of testis tissue regeneration. We collected newborn piglet testes after routine castration, used enzymes to completely dissociate testis cells, exposed the cells to two key growth factors (EGF or GDNF), and implanted the cells under the back skin of recipient mice, acting as live incubators. We then examined implant samples after 1, 2, 4, or 8 weeks and assessed testis regeneration. Overall, the high dose of each growth factor had adverse effects on the formation of normal testis. Therefore, this novel implantation model may also be used to study the effects of potentially harmful substances on testis development.

Melatonin promotes apoptosis of thyroid cancer cells via regulating the signaling of microRNA-21 (miR-21) and microRNA-30e (miR-30e).

Melatonin (MEL) is an effective therapeutic choice for thyroid cancer treatment. In this study, we aimed to explored the potential effect of MEL upon the drug sensitivity of cancer cells and the according underlying mechanisms. Thyroid cancer mice were established as a control group and a MEL group to observe the in vivo effect of MEL. Tumor size and weight in nude mice were detected to evaluate the effect of MEL on tumor growth. Immunohistochemistry assay (IHC) and Western blot were performed to analyze the expression of PTEN protein in tumor cells or tumor cells. After 32 days of cancer cell implantation, MEL was found to significantly repress tumor growth in nude mice approximately by half. Moreover, MEL also suppressed tumor cell proliferation, while apparently activating the apoptosis of tumor cells. In addition, hydrogen sulfide (H2S) production was obviously elevated by MEL treatment. Mechanistically, the expression of phosphatase and tensin homolog (PTEN) was remarkably activated by MEL treatment in tumor tissues of implanted TPC-1 and BCPaP cells in nude mice. Meanwhile, MEL inhibited the expression of miR-21 and miR-30e and promoted the expression of lncRNA-cancer susceptibility candidate 7 (CASC7). Both miR-21 and miR-30e could suppress PTEN expression, while miR-21 could also inhibit the expression of lncRNA-CASC7. In conclusion, the results demonstrated that the MEL administration could downregulate the expression of miR-21 and miR-30e, which resulted in increased expression of PTEN, a pro-apoptotic tumor suppressor, to promote the apoptosis of thyroid cancer cells.

Updates on mesenchymal stem cell therapies for articular cartilage regeneration in large animal models.

There is an unmet need for novel and efficacious therapeutics for regenerating injured articular cartilage in progressive osteoarthritis (OA) and/or trauma. Mesenchymal stem cells (MSCs) are particularly promising for their chondrogenic differentiation, local healing environment modulation, and tissue- and organism-specific activity; however, despite early in vivo success, MSCs require further investigation in highly-translatable models prior to disseminated clinical usage. Large animal models, such as canine, porcine, ruminant, and equine models, are particularly valuable for studying allogenic and xenogenic human MSCs in a human-like osteochondral microenvironment, and thus play a critical role in identifying promising approaches for subsequent clinical investigation. In this mini-review, we focus on [1] considerations for MSC-harnessing studies in each large animal model, [2] source tissues and organisms of MSCs for large animal studies, and [3] tissue engineering strategies for optimizing MSC-based cartilage regeneration in large animal models, with a focus on research published within the last 5 years. We also highlight the dearth of standard assessments and protocols regarding several crucial aspects of MSC-harnessing cartilage regeneration in large animal models, and call for further research to maximize the translatability of future MSC findings.

Long-Term Monitoring of Donor Xenogeneic Testis Tissue Grafts and Cell Implants in Recipient Mice Using Ultrasound Biomicroscopy.

Testis tissue xenografting and testis cell aggregate implantation from various donor species into recipient mice are novel models for the study and manipulation of testis formation and function in target species. Thus far, the analysis of such studies has been limited to surgical or post-mortem retrieval of samples. Here we used ultrasound biomicroscopy (UBM) to monitor the development of neonatal porcine testis grafts and implants in host mice for 24 wk, and to correlate UBM and (immuno)histologic changes. This led to long-term visualization of gradual changes in volume, dimension and structure of grafts and implants; detection of a 4 wk developmental gap between grafts and implants; and revelation of differences in implant development depending on the craniocaudal site of implantation on the back of host mice. Our data support the reliability and precision of UBM for longitudinal study of transplants, which eliminates the need for frequent surgical sampling.

Validation of ultrasound biomicroscopy for the assessment of xenogeneic testis tissue grafts and cell implants in recipient mice.

BACKGROUND: Subcutaneous grafting/implantation of neonatal testis tissue/cells from diverse donor species into recipient mice can be used as an in vivo model to study testis development, spermatogenesis, and steroidogenesis. Ultrasound biomicroscopy (UBM) allows obtaining high definition cross-sectional images of tissues at microscopic resolutions. OBJECTIVES: The present study was designed to (a) validate the use of UBM for non-invasive monitoring of grafts/implants overtime and to (b) correlate UBM findings with the morphological attributes of recovered grafts/implants. MATERIALS AND METHODS: Testis tissue fragments (~14 mm3 , each) and cell aggregates (100 × 106 cells, each) obtained from 1-week-old donor piglets (n = 30) were grafted/implanted under the back skin of immunodeficient mice (n = 6) in eight analogous sites per mouse. Three-dimensional transcutaneous Doppler UBM was performed, and a randomly selected graft and its corresponding implant were recovered at 2, 4, 6, and 8 weeks. RESULTS: Graft/implant weight (P = .04) and physical height (P = .03) increased overtime. The dynamics of physical length and volume increases over time differed between tissue grafts and cell implants (P = .02 and 0.01 for sample type*time interactions, respectively). UBM-estimated volume was correlated with the post-recovery weight and volume of the grafts/implants (r = 0.98 and r = 0.99, respectively; P < .001). Pre- and post-recovery length and height of the grafts/implants were positively and strongly correlated (r = 0.50, P = .01; r = 0.70, P = .001) and so were the areas covered by cordal, non-cordal, or fluid-filled cavities between UBM and histology (r = 0.87, P < .001). DISCUSSION AND CONCLUSION: UBM findings correlated with physical attributes of the grafts/implants, validating its use as a non-invasive high-fidelity tool to quantify the developmental changes in ectopic testis tissue grafts and cell implants, potentially leading to a reduction in the number of recipient mice needed for similar experiments.

Stem cell therapy for osteonecrosis of femoral head: Opportunities and challenges.

Osteonecrosis of the femoral head (ONFH) is a progressive disease with a complex etiology and unclear pathogenesis, resulting in severe hip pain and dysfunction mainly observed in young patients. Although total hip arthroplasty (THA) is the most effective treatment for patients with ONFH in the terminal stage, the results of THA in young patients or active populations are often not favorable, with some complications related to the prosthesis. With the development of biotechnology, an increasing number of studies pay attention to use of stem cells for the treatment of ONFH. Stem cells are characterized by the ability to self-renew and differentiate into multiple cell types, including differentiation into osteoblasts and endothelial cells to mediate bone repair and angiogenesis. Furthermore, stem cells can offer growth factors to promote blood supply in the necrotic regions by paracrine effects. Therefore, stem cell therapy has become one of the hip-preserving alternatives for ONFH. This review summarized the current trends in stem cell therapy for ONFH, from clinical applications to related basic research, and showed that an increasing number of studies have confirmed the effectiveness of stem cell therapy in ONFH. However, many unsolved problems and challenges in practical applications of stem cell therapy still exist, such as patient selection, standardized procedures, safety assessment, and the fate of transplanted cells in the body. Additional studies are required to find ideal cell sources, appropriate transplantation methods, and the optimal number of cells for transplantation.

Calvarial Bone Implantation and in vivo Imaging of Tumor Cells in Mice.

Bone is one of common metastasis sites for many types of cancer. In bone metastatic microenvironment, tumor-bone interactions play a significant role in the regulation of osteolytic or osteoblastic bone metastasis. In order to investigate the direct interaction between tumor cells and bone tissue, it is essential to generate appropriate animal models that mimic the behavior of tumor cells in bone metastatic lesions. Calvarial implantation model (bone invasion model) is a newly-established animal model that accurately recapitulates the behavior of tumor cells in the tumor-bone microenvironment. The surgical technique for tumor cell implantation is simpler than intracardiac, intra-arterial, or intraosseous injection techniques. This model can be useful for the identification of key factors driving tumor-induced osteolytic or osteoblastic changes.

The in vivo timeline of differentiation of engrafted human neural progenitor cells.

Understanding the individual timeline of stem cell differentiation in vivo is critical for evaluating stem cell properties in animal models. However, with conventional ex vivo techniques, such as histology, the individual timeline of differentiation is not accessible. Therefore, we designed lentiviral plasmids with cell-specific promoters to control the expression of bioluminescence and fluorescence imaging reporters. Promoter-dependent reporter expression in transduced human induced pluripotent stem cell-derived neural progenitor cells (hNPCs) was an effective indicator of differentiation in cell culture. A 12-week in vivo imaging observation period revealed the time profile of differentiation of engrafted hNPCs in the mouse brain into astrocytes and mature neurons which was verified by immunostainings, patch-clamp electrophysiology, and light-sheet fluorescence microscopy. The lentiviral vectors validated in this study provide an efficient imaging toolbox for non-invasive and longitudinal characterization of stem cell differentiation, in vitro screenings, and in vivo studies of cell therapy in animal models.

In vivo annular repair using high-density collagen gel seeded with annulus fibrosus cells.

OBJECTIVE: The aim is assessing the in vivo efficacy of annulus fibrosus (AF) cells seeded into collagen by enhancing the reparative process around annular defects and preventing further degeneration in a rat-tail model. SUMMARY OF BACKGROUND DATA: Treating disc herniation with discectomy may relieve the related symptoms but does not address the underlying pathology. The persistent annular defect may lead to re-herniation and further degeneration. We recently demonstrated that riboflavin crosslinked high-density collagen gels (HDC) can facilitate annular repair in vivo. METHODS: 42 rats, tail disc punctured with an 18-gauge needle, were divided into 3 groups: untreated (n = 6), injected with crosslinked HDC (n = 18), and injected with AF cell-laden crosslinked HDC (n = 18). Ovine AF cells were mixed with HDC gels prior to injection. X-rays and MRIs were conducted over 5 weeks, determining disc height index (DHI), nucleus pulposus (NP) size, and hydration. Histological assessments evaluated the viability of implanted cells and degree of annular repair. RESULTS: Although average DHIs of both HDC gel groups were higher than those of the puncture control group at 5 weeks, the retention of disc height, NP size and hydration at 1 and 5 weeks was significant for the cellular group compared to the punctured, and at 5 weeks to the acellular group. Histological assessment indicated that AF cell-laden HDC gels have accelerated reparative sealing compared to acellular HDC gels. CONCLUSIONS: AF cell-laden HDC gels have the ability of better repairing annular defects than acellular gels after needle puncture. STATEMENT OF SIGNIFICANCE: This project addresses the compelling demand of a sufficient treatment strategy for degenerative disc disease (DDD) perpetuated by annulus fibrosus (AF) injury, a major cause of morbidity and burden to health care systems. Our study is designed to answer the question of whether injectable, photo-crosslinked, high density collagen gels can seal defects in the annulus fibrosus of rats and prevent disc degeneration. Furthermore, we investigated whether the healing of AF defects will be enhanced by the delivery of AF cells (fibrochondrocytes) to these defects. The use of cell-laden collagen gels in spine surgery holds promise for a wide array of applications, from current discectomy procedures to future nucleus pulposus reparative therapies, and our group is excited about this potential.

Stem cell therapy for faecal incontinence: Current state and future perspectives.

Faecal continence is a complex function involving different organs and systems. Faecal incontinence is a common disorder with different pathogeneses, disabling consequences and high repercussions for quality of life. Current management modalities are not ideal, and the development of new treatments is needed. Since 2008, stem cell therapies have been validated, 36 publications have appeared (29 in preclinical models and seven in clinical settings), and six registered clinical trials are currently ongoing. Some publications have combined stem cells with bioengineering technologies. The aim of this review is to identify and summarise the existing published knowledge of stem cell utilization as a treatment for faecal incontinence. A narrative or descriptive review is presented. Preclinical studies have demonstrated that cellular therapy, mainly in the form of local injections of muscle-derived (muscle derived stem cells or myoblasts derived from them) or mesenchymal (bone-marrow- or adipose-derived) stem cells, is safe. Cellular therapy has also been shown to stimulate the repair of both acute and subacute anal sphincter injuries, and some encouraging functional results have been obtained. Stem cells combined with normal cells on bioengineered scaffolds have achieved the successful creation and implantation of intrinsically-innervated anal sphincter constructs. The clinical evidence, based on adipose-derived stem cells and myoblasts, is extremely limited yet has yielded some promising results, and appears to be safe. Further investigation in both animal models and clinical settings is necessary to drawing conclusions. Nevertheless, if the preliminary results are confirmed, stem cell therapy for faecal incontinence may well become a clinical reality in the near future.