Injection Of Stem Cells Research Articles

ECM-Inspired Hydrogels with ADSCs Encapsulation for Rheumatoid Arthritis Treatment.

Due to their intrinsic anti-inflammatory and immunomodulatory properties, adipose-derived stem cells (ADSCs) are explored as a promising alternative in treating rheumatoid arthritis (RA). To address the poor survival and function loss of directly injected stem cells, efforts in this area are focus on the generation of efficient cell delivery vehicles. Herein, a novel extracellular matrix (ECM)-inspired injectable hydrogel for ADSCs encapsulation and RA treatment is proposed. The hydrogel with dendritic polylysine and polysaccharide components is formed through the reversible Schiff base crosslinking. It possesses self-healing capability, superior mechanical properties, minimal toxicity, and immunomodulatory ability. When encapsulated with ADSCs, the hydrogel could recover chronic inflammation by directly reversing the dominant macrophage phenotype from M1 to M2 and inhibiting the migration of fibroblast-like synoviocytes. Through a collagen-induced arthritis rat model, the tremendous therapeutic outcomes of this ADSCs-laden hydrogel, including inflammation attenuation, cartilage protection, and bone mineral density promotion are demonstrated. These results make the ECM-inspired hydrogel laden with ADSCs an ideal candidate for treating RA and other autoimmune disorders.

Naturally derived injectable hydrogels with ROS-scavenging property to protect transplanted stem cell bioactivity for osteoarthritic cartilage repair.

Intra-articular injection of adipose mesenchymal stem cells (ADSCs) is a potential alternative to the treatment of osteoarthritis (OA) and has aroused great interest of clinical researchers. However, the hostile microenvironment in the joint cavity, characterized by reactive oxygen species (ROS) accumulation and excessive inflammation, disturbs the bioactivity of the transplanted stem cells. The (-)-epigallocatechin-3-O-gallate (EGCG), a green tea catechin, has attracted the researchers' attention owing to its powerful ROS-scavenging and antioxidant properties. In this study, to avoid rapid degradation and/or depletion of EGCG, we prepare a long-lasting injectable hydrogel by EGCG and hyaluronic acid (HA). The naturally derived hydrogels with excellent biocompatibility and durable retention time can capture the redundant ROS continuously and efficiently, thus protecting ADSCs from ROS-mediated death and bioactivity inhibition, including cell survival, proliferation and chondrogenic differentiation. Intra-articular injection of this ADSCs loaded hydrogel significantly induced synovial macrophages polarization to M2 phenotype, decreased pro-inflammatory cytokines (e.g., IL-1β, MMP-13, and TNF-α) expression, promoted cartilage matrix formation, and repaired cartilage destruction in OA. This stem cell-protected hydrogel delivery strategy showed superior efficacy than ADSCs delivering or EGCG-HA injection singly, which providing a potential alternative strategy for OA management.

Invasive Non-Arthroplasty Treatment Options for Knee Osteoarthritis: Review

Introduction: Knee osteoarthritis (KOA) is one of the most common joint diseases in the world, such that there exists a variety of treatment methods, ranging from conservative treatments such as physical therapy and weight loss to total replacement of the diseased joint. Invasive non-arthroplasty treatment methods are growing in popularity and this review aims to explore the current literature. Better understanding of these alternatives could allow orthopedic surgeons and primary care providers to offer poor arthroplasty candidates meaningful symptomatic relief. Materials and Methods: A literature review using PubMed, Google Scholar, and SCOPUS was performed to examine the following invasive non-arthroplasty treatment options: Corticosteroid injections (CS), viscosupplementation, platelet-rich plasma injections, stem cell injections, ozone therapy, prolotherapy, radiofrequency nerve ablation (RFA), arthroscopy, and osteotomy. Articles with complete data on the outcomes following these treatment methods were included in the study. Results: CSs showed strong efficacy in providing short-term pain relief, while viscosupplementation and platelet-rich plasma have shown to be effective in long-term management as well. Aside from the more common injectable treatment options, newer options such as stem cell injection and ozone therapy have shown clinical efficacy while prolotherapy and RFA are still early-stage treatment options. Still, further studies are required to better assess these emerging therapies. Operatively, arthroscopic surgery has shown to be minimally effective while osteotomy demonstrated effective pain and functional improvement. Conclusion: Multiple therapeutic options exist for invasive management of KOA to a different degree of effectiveness and efficacy. We have analyzed the outcomes of multiple invasive non-arthroplasty treatment options for KOA. This review can better inform patients and surgeons of the pros and cons of different KOA treatment methods. Newer conservative options may have positive clinical implications but will require further investigation. Operative alternatives to arthroplasty can provide symptomatic relief but may increase the associated risk and complexity should the need for arthroplasty ever arises. Keywords: Total knee arthroplasty, injections, radiofrequency nerve ablation, arthroscopy, osteotomy.

Intra-articular injection of human umbilical cord-derived mesenchymal stem cells in sheep models of meniscectomy-induced osteoarthritis: An experimental study

Introduction: Autologous mesenchymal stem cells (MSC) implantation suspended in hyaluronic acid (HA) has been proven to delay worsening of articular cartilage degeneration in the knee joint. This has been the treatment of choice for young patients with knee osteoarthritis (KOA); however, it is associated with morbidities such as requirement of multiple procedures, donor site morbidity and failure in achieving cultured cells with chondrogenic properties. Our study investigates the possibility of direct intra articular injection of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) for sheep models of meniscectomy-induced osteoarthritis. Methods: Twelve sheeps with the same characteristics was osteoarthritically induced with lateral meniscectomy and a series of routine exercise. Those sheep were divided into four groups with 3 sheep each. The groups are the control group, intra articular HA (hyalgan G-F 20; Synvisc®) injection group, intra articular hUC-MSCs group, intra articular hUC-MSCs suspended in HA group. The sheeps were sacrificed four weeks post-treatment for gross pathology and histopathology graded according to the Osteoarthritic Research Society International (OARSI) system. Results: The intra articular hUC-MSCs suspended in HA group showed better gross pathology and histopathology grade compared to control groups (p<0.05) according to the OARSI system. The hUC-MSCs suspended in HA group microscopically showed superior chondrocyte number and varying degrees of cellular regeneration of articular cartilage. Conclusion: The use of intra articular hUC-MSCs suspended in HA is an option in treating KOA. Its efficacy in articular cartilage regeneration would be further explained in clinical trials.

Enhancement of Anterior Cruciate ligament Reconstruction using Mesenchymal Stem Cells

One of the most common injuries in orthopaedic field is anterior cruciate ligament (ACL) tear, which accounts for more than 50% of all knee injuries and has an estimated incidence rate of 60.9 per 100,000 persons. Untreated ACL injuries may lead to postural instability, increase in meniscal injury rates, and osteoarthritis that develops more gradually. The gold standard treatment for ACL tears is arthroscopic reconstruction using an autograft or allograft tendon. However, graft failure during an ACL reconstruction (ACLR) can considerably delay recovery and lead to revision ACLR operation that has worse prognosis. A number of regenerative techniques, including stem cells, biomaterials, and bioactive compounds, have been researched and shown to be efficient. The injection of stem cells as biological augmentation has been suggested as a method to enhance the results of ACLR. Mesenchymal stem cells (MSC) in particular can differentiate into a number of terminally differentiated progenitors that can be used to create mesenchymal-derived tissues and to speed up the healing process by influence the microenvironment to promote angiogenesis, promote regeneration, and prevent the formation of scar tissue. The goal of this study is to outline the present use of stem cells as an augmentation in ACLR.

Ultrasound monitoring of the regenerative treatment of Biceps Tendonitis and Tenosynovitis in dogs by stem cells injections

Injuries and the overloading of the bicipital muscle tendon in dogs are a common cause of Bicipital Tendinitis and Tenosynovitis (BBT). The aim of the study was to evaluate the advantage of ultrasound monitoring during regenerative treatment of BBT together with treatment assessment by dog owners. 32 dogs of both sexes were used in the study. The dogs were treated with adipose-derived mesenchymal stem cells with platelet-rich plasma (ADMSC + PRP) administered twice in a dose of 0.5 ml (15.0 × 106 cells/ml). The ADMSC + PRP was injected into the tendon sheath of the biceps and 0.5 ml was injected into the brachial joint cavity. During the research, pain evaluation was performed according to the Canine Brief Pain Inventor – Penn CHART (CBPI), ultrasound scans were also performed. Some of the changes in ultrasound images are permanent and the recovery is gradual and incomplete. The research showed a correlation between the results of the ultrasound scans and the owners of the CBPI questionnaire, this was correlated with the effects of regenerative therapy. Studies have shown the regenerative effect of ADMSC + PRP on the tendon sheath and biceps tendon of the brachii after 4 months.

Combining biomimetic collagen/hyaluronan hydrogels with discogenic growth factors promotes mesenchymal stroma cell differentiation into Nucleus Pulposus like cells.

Based on stem cell injection into degenerated Nucleus Pulposus (NP), novel treatments for intervertebral disc (IVD) regeneration were disappointing because of cell leakage or inappropriate cell differentiation. In this study, we hypothesized that mesenchymal stromal cells encapsulated within injectable hydrogels possessing adequate physico-chemical properties would differentiate into NP like cells. Composite hydrogels consisting of type I collagen and tyramine-substituted hyaluronic acid (THA) were prepared to mimic the NP physico-chemical properties. Human bone marrow derived mesenchymal stromal cells (BM-MSCs) were encapsulated within hydrogels and cultivated in proliferation medium (supplemented with 10% fetal bovine serum) or differentiation medium (supplemented with GDF5 and TGFβ1) over 28 days. Unlike pure collagen, collagen/THA composite hydrogels were stable over 28 days in culture. In proliferation medium, the cell viability within pure collagen hydrogels was high, whereas that in composite and pure THA hydrogels was lower due to the weaker cell adhesion. Nonetheless, BM-MSCs proliferated in all hydrogels. In composite hydrogels, cells exhibited a rounded morphology similar to NP cells. The differentiation medium did not impact the hydrogel stability and cell morphology but negatively impacted the cell viability in pure collagen hydrogels. A high THA content within hydrogels promoted the gene expression of NP markers such as collagen II, aggrecan, SOX9 and cytokeratin 18 at day 28. The differentiation medium potentialized this effect with an earlier and higher expression of these NP markers. Taken together, these results show that the physico-chemical properties of collagen/THA composite hydrogels and GDF5/TGFβ1 act in synergy to promote the differentiation of BM-MSCs into NP like cells.

Ultrasound monitoring of the regenerative treatment of Biceps Tendonitis and Tenosynovitis in dogs by stem cells injections

Foot-and-mouth disease (FMD) and bluetongue disease (BT) are two of the most devastating viral diseases affecting domestic and wild ruminants. They cause significant economic losses, and vaccination is the most important method for combating both FMD and BT. Simultaneous vaccinations are crucial for animal welfare as well as labor and cost savings. No reports were found on the simultaneous administration of FMD and BT vaccines to sheep. This study evaluated the effect of the simultaneous administration of an inactivated FMD vaccine and an attenuated BT vaccine on the humoral immune response to both diseases. A total of 75 sixmonth- old Akkaraman-Kıvırcık crossbred sheep that did not have any vaccination history were used as research material. Before the experiment, the animals were tested for the absence of FMD and BT antibodies. The sheep were divided into three experimental groups and vaccinated with an FMD vaccine alone, a BT vaccine alone, and both. Blood samples were taken on days 30 and 60 post-vaccination. The blood samples were evaluated using liquid-phase blocking ELISA (LPBE) and virus neutralization test (VNT) for FMD antibodies, as well as competitive ELISA (c-ELISA) and VNT for BT antibodies. The study revealed that differences between the FMD and BT antibody titers of the group vaccinated simultaneously and the FMD and BT antibody titers obtained from the groups vaccinated separately were not statistically significant (p > 0.05). It was concluded that the antibody response these diseases was not altered when the FMD and BT vaccines were administered together.

Wharton's jelly mesenchymal stem cells attenuate global hypoxia-induced learning and memory impairment via preventing blood-brain barrier breakdown.

Intracerebroventricular (ICV) injections of mesenchymal stem cells (MSCs) may improve the function and structure of blood-brain barrier (BBB), possibly by preserving the BBB integrity. This study examined the impact of Wharton's jelly (WJ)-MSCs on cognitive dysfunction and BBB disruption following a protracted hypoxic state. Twenty-four male Wistar rats were randomly studied in four groups: Control (Co): Healthy animals, Sham (Sh): Rats were placed in the cage without hypoxia induction and with ICV injection of vehicle, Hypoxic (Hx)+vehicle: Hypoxic rats with ICV injection of vehicle (5 μl of PBS), and Hx+MSCs: Hypoxic rats with ICV injection of MSCs. Spatial learning and memory were evaluated one week after WJ-MSCs injection, and then animals were sacrificed for molecular research. Hypoxia increased latency and lowered the time and distance required reaching the target quarter, according to the findings. Furthermore, hypoxic rats had lower gene expression and protein levels of hippocampus vascular endothelial (VE)-cadherin, claudin 5, and tricellulin gene expression than Co and Sh animals (P<0.05). Finally, administering WJ-MSCs after long-term hypoxia effectively reversed the cognitive deficits and prevented the BBB breakdown via the upregulation of VE-cadherin, claudin 5, and tricellulin genes (P<0.05). These findings suggest that prolonged hypoxia induces spatial learning and memory dysfunction and increases BBB disruption, the potential mechanism of which might be via reducing VE-cadherin, claudin 5, and tricellulin genes. Hence, appropriate treatment with WJ-MSCs could reverse ischemia adverse effects and protect the BBB integrity following prolonged hypoxia.

Exosomal miR-23b from bone marrow mesenchymal stem cells alleviates oxidative stress and pyroptosis after intracerebral hemorrhage.

Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage (ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase VII into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3 (NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH.

Stem-cell therapy in stress urinary incontinence: A review.

The incidence of urinary incontinence (UI) is approximately 10%-40% in women, affecting one to two hundred million women worldwide. Stress UI (SUI) is characterized by involuntary urination due to increased abdominal stress and urine leakage without bladder contraction. Surgical treatments include midurethral slings, bulking agents, and Burch colposuspension to restore urethral continence. Nevertheless, an optimal treatment for all types of incontinence has not yet been established. Stem-cell therapy has emerged as a novel treatment for many diseases. Stem cells can self-renew and can differentiate into other cell types. Adult stem cells are suitable for clinical applications because they can be easily obtained noninvasively or minimal invasively. Stem-cell therapy for SUI has been studied preclinically and clinically. Muscle-derived progenitors have been used to treat SUI by promoting the regeneration of rhabdomyosphincters. The human trial used transurethral injection of autologous muscle-derived stem cells to improve sphincter contractility and function. Other sources of stem cells have also been studied in SUI treatment, such as umbilical cord blood, amniotic fluid, bone marrow, urine, and adipose tissue. The success rate of stem-cell therapy for SUI ranges from 13% to 100%. This review aimed to summarize the current status of stem-cell treatments for SUI, with respect to clinical trials, cell types, transplantation routes, and dosage volume and frequency.

Comparing Periurethral Injection of Autologous Muscle-Derived Stem Cell and Fibroblasts with Mid-Urethral Sling Surgery in the Treatment of Female Stress Urinary Incontinence: A Randomized Clinical Trial.

In this study, we analyzed the therapeutic effect of periurethral injection of autologous muscle-derived stem cell versus mid-urethral sling surgery at a 1-year follow-up. This randomized controlled clinical trial was conducted on 30 women with stress urinary incontinence (SUI) who had not responded to conservative treatments, after registering the participants and obtaining informed consent. Patients were divided into two groups of 15 each treated with periurethral injection of muscle-derived stem cells (MDSCs) and mid-urethral sling surgery, respectively. Follow-ups were done at 1, 3, 6, and 12 months after the treatment using the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UISF) and Incontinence Quality of Life Questionnaire (I-QOL) questionnaires, clinical examination, cough test, and 1-hour pad test. The results were analyzed within the groups and then compared between the two groups. Moreover, both groups were compared in terms of postoperative complications. At the 1-year follow-up, in the stem cell group, 10 patients (66.6%) experienced improvements after the periurethral injection of stem cells; half of these patients (33.3%) reported a full recovery. In the mid-urethral sling group, 13 patients (93.3%) experienced improvement, and 12 patients (80%) reported a full recovery. The analysis of ICIQ-UISF and I-QOL questionnaires indicated that the responses in both groups were significant, but the response in the stem cell group was significantly lower compared with the standard surgery group. No considerable complications were observed in the two groups. Although the periurethral injection of MDSCs considerably improves the symptoms with minimum complications in women with SUI, its therapeutic response is significantly lower compared with mid-urethral sling surgery.

Feasibility of minimally invasive, same-day injection of autologous adipose-derived stem cells in the treatment of erectile dysfunction

Objective To investigate feasibility and safety of a new minimally invasive same-day method of autologous adipose derived stem cell (ADSC) transplantation in men suffering from ED. Materials and methods Prospective case series of 10 men with an IIEF-EF domain score <17. The IIEF questionnaire was filled out at baseline and 1, 2 and 3 months after treatment. Side effects were assessed by investigations and interviews until 6 months after treatment. The myStem® X2 kit was used for preparation of ADSC: Adipose tissue was harvested from the patient himself under local anesthesia and immediately prepared and injected into the penis. Primary endpoints were feasibility and safety. Secondary outcomes included effects on ED and changes in the remaining IIEF domains. Results Ten men were included. Only one adverse event in the form of minor blue discoloration at the fat harvest site was registered. There were statistically significant improvements in IIEF-EF at one, two and three months after treatment compared to baseline with the median score increasing from 5.5 to 10.5, 10.5 and 10, respectively. Considering the individual patients, 3/10 men achieved an improvement equal to or greater than the minimal clinically important difference according to their baseline IIEF-EF score. Conclusions Our study confirms the feasibility and safety of this minimally invasive, same-day delivery of ADSC. Due to the design and size on the study, conclusions should not be drawn regarding efficacy, but the method seems worthy of further study.

1222. Summary of CDC consultations related to non-traditional medical therapies, 2016─2021

Abstract Background Non-traditional medical therapies, which include invasive or parenteral therapies for unapproved conditions, such as stem cell joint injections and certain cosmetic procedures may lack regulatory oversight and pose infectious risks to patients. We aimed to describe Centers for Disease Control and Prevention (CDC) consultations involving outbreaks or infection control lapses that involved non-traditional medical therapies to identify areas for prevention efforts. Methods We reviewed internal CDC records from January 1, 2016, through December 31, 2021, to identify consultations that involved investigations of disease transmission and infection control lapses involving non-traditional medical therapies in U.S. settings. We included consultations involving therapies and procedures such as facials, fillers, microneedling, intravenous hydration, vitamin infusions, platelet-rich plasma (PRP), and stem cell injections. We determined number of consultations and patients infected or exposed to infection control lapses, infection types, types of procedures implicated, pathogen of concern, and whether at-risk patients were notified. Results We identified 25 consultations that met inclusion criteria; 22 involved 65 infected patients and 3 involved infection control lapses without identified infections. Infection types included joint (n=8, 32%), skin and soft tissue (5, 20%), and bloodstream (3, 12%). The most common pathogens implicated included nontuberculous mycobacteria (3, 12%), hepatitis C virus (3, 12%), and several Enterobacterales (6, 24%). Therapies most frequently involved included PRP or stem cell joint injections (9, 36%), vitamin infusions/injections (4, 16%), and aesthetic treatments (6, 24%). Settings most commonly involved chiropractic clinics (3, 12%), pain clinics (3, 12%), medical spas (2, 8%), orthopedic clinics (2, 8%), and aesthetics clinics (2, 8%). Conclusion Lapses in infection control practices involving non-traditional medical therapies have the potential to place patients at significant risk of infection. Targeting infection control education and oversight to settings where these procedures commonly take place may help reduce patient risk. Disclosures All Authors: No reported disclosures.

Synovium-Derived Mesenchymal Stem Cells in Combination with Low Molecular Weight Hyaluronic Acid for Cartilage Repair

Regeneration of damaged articular cartilage remains one of the most complex and unresolved problems in traumatology and orthopedics. In this study, we investigated whether intra-articular injection of synovium-derived mesenchymal stem cells (SD-MSCs) with low molecular weight hyaluronic acid (LMWHA) could promote the regeneration of damaged cartilage in rabbits. To answer this question, rabbits' SD-MSCs were harvested, expanded in culture, and characterized by CFU assay and a multilineage differentiation test. For in vivo study, we created a defect within the cartilage layer without destroying subchondral bone. Two weeks after the cartilage defect, SD-MSCs (2×106 cells) were suspended in 0.5% LMWHA and injected into the left knee, and hyaluronic acid (HA) solution alone was placed into the right knee. Cartilage regeneration in experimental and control groups was evaluated macroscopically and histologically at Days 30, 60, and 90. The results of the study showed an early process of cartilage regeneration in the defect area on Day 30 after intra-articular MSCs-HA injection. Histological studies revealed that cartilage defect was covered by a thin layer of spindle-shaped undifferentiated cells and proliferated chondroblasts, in contrast to a single HA injection, which did not induce cartilage regeneration. On Day 60, we observed that the size of the cartilage defect after MSCs-HA injection significantly decreased, compared to one after HA injection. On Day 90, the cartilage defect in a knee treated with MSCs-HA was fully regenerated and was similar to intact cartilage. Thus, the combined application of the MSCs, HA, and chondroinductive proteins have a high therapeutic effect on cartilage defect regeneration in rabbits.

Noncontact 3-D Orientation Control at Microscale: Hydrodynamic Out-of-Plane Rotation and In-Plane Rotation by Compacted Rotational Stage

In cloning, clinical <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vitro</i> fertilization, gene research, and stem cell research, enucleation or injection of the individual cell is essential. Three-dimensional (3-D) orientation control of the target cell could significantly influence the operation success rate, which is still one of the main challenges in conventional micromanipulation. In this article, we give a cost-effective solution of the 3-D orientation control at the microscale combining the hydrodynamic out-of-plane rotation and the in-plane rotation by compacted rotational stage. We equipped a standard microinjection system with a single piezo-actuator and a 3-D printed compacted rotational stage. Using the resonance of the designed copper cantilever as the pipette holder and the Lissajous Principle, we extended the 1-D oscillation of the piezo-actuator to 2-D circular oscillation of the injecting micropipette. The circular oscillation could generate a whirling flow for noncontact immobilization and out-of-plane rotation of the target. After the out-of-plane rotation, the rotational stage was employed to realize the in-plane rotation, and a holding-position control strategy was proposed to compensate circular motion in global of the target. The performance of these two rotation methods has been tested by rotating microbeads with outer diameters of 98 <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">μ</i> m. 3-D orientation control of the microbead and the mouse oocyte has been achieved, which indicates that the proposed method could be widely applied in the biomedical field.

Is TGR5 a therapeutic target for the treatment of spinal cordinjury?

Bile acids, which are synthesized in liver and colon, facilitate the digestion of dietary lipids. In addition to this metabolic function, they also act as molecular signals with activities in the nervous system. These are mediated primarily by a G-protein-coupled bile acid receptor (known as TGR5). Preceded by a long tradition in Chinese medicine, bile acids are now being investigated as therapeutic options in several neuropathologies. Specifically, one bile acid, tauroursodeoxycholic acid (TUDCA), which passes the blood-brain barrier and shows anti-inflammatory and anti-apoptotic effects, has been tested in animal models of spinal cord injury (SCI). In this review, we discuss the evidence for a therapeutic benefit in these preclinical experiments. At the time of writing, 12 studies with TGR5 agonists have been published that report functional outcomes with rodent models of SCI. Most investigations found cytoprotective effects and benefits regarding the recovery of sensorimotor function in the subacute phase. When TUDCA was applied in a hydrogel into the lesion site, a significant improvement was obtained at 2 weeks after SCI. However, no lasting improvements with TUDCA treatment were found, when animals were assessed in later, chronic stages. A combination of TUDCA with stem cell injection failed to improve the effect of the cellular treatment. We conclude that the evidence does not support the use of TUDCA as a treatment of SCI. Nevertheless, cytoprotective effects suggest that different modes of application or combinatorial therapies might still be explored.

Intraarticular Injections of Mesenchymal Stem Cells in Knee Osteoarthritis: A Review of Their Current Molecular Mechanisms of Action and Their Efficacy

More than 10% of the world's population suffers from osteoarthritis (OA) of the knee, with a lifetime risk of 45%. Current treatments for knee OA pain are as follows: weight control; oral pharmacological treatment (non-steroidal anti-inflammatory drugs, paracetamol, opioids); mechanical aids (crutches, walkers, braces, orthotics); therapeutic physical exercise; and intraarticular injections of corticosteroids, hyaluronic acid, and platelet-rich plasma (PRP). The problem is that such treatments usually relieve joint pain for only a short period of time. With respect to intraarticular injections, corticosteroids relieve pain for several weeks, while hyaluronic acid and PRP relieve pain for several months. When the above treatments fail to control knee pain, total knee arthroplasty (TKA) is usually indicated; however, although a very effective surgical technique, it can be associated with medical and postoperative (surgery-related) complications. Therefore, it seems essential to look for safe and effective alternative treatments to TKA. Recently, there has been much research on intraarticular injections of mesenchymal stem cells (MSCs) for the management of OA of the knee joint. This article reviews the latest information on the molecular mechanisms of action of MSCs and their potential therapeutic benefit in clinical practice in patients with painful knee OA. Although most recent publications claim that intraarticular injections of MSCs relieve joint pain in the short term, their efficacy remains controversial given that the existing scientific information on MSCs is indecisive. Before recommending intraarticular MSCs injections routinely in patients with painful knee OA, more studies comparing MSCs with placebo are needed. Furthermore, a standard protocol for intraarticular injections of MSCs in knee OA is needed.

Application of stem cells combined with biomaterial in the treatment of intervertebral disc degeneration.

As the world population is aging, intervertebral disc degeneration (IDD) is becoming a global health issue of increasing concern. A variety of disc degeneration diseases (DDDs) have been proven to be associated with IDD, and these illnesses have significant adverse effects on both individuals and society. The application of stem cells in regenerative medicine, such as blood and circulation, has been demonstrated by numerous studies. Similarly, stem cells have made exciting progress in the treatment of IDD. However, due to complex anatomical structures and functional requirements, traditional stem cell injection makes it difficult to meet people's expectations. With the continuous development of tissue engineering and biomaterials, stem cell combined with biomaterials has far more prospects than before. This review aims to objectively and comprehensively summarize the development of stem cells combined with contemporary biomaterials and the difficulties that need to be overcome.

The Effect of Different Frequencies of Pulsed Electromagnetic Fields on Cartilage Repair of Adipose Mesenchymal Stem Cell-Derived Exosomes in Osteoarthritis.

The intra-articular injection of mesenchymal stem cell (MSC)-derived exosomes has already been proved to reverse osteoarthritic cartilage degeneration. Pulsed electromagnetic field (PEMF) has been found to regulate the biogenic function of MSCs. However, the effect of PEMF on MSC-derived exosomes has not yet been characterized. The aim of this study was to elucidate the regulatory role of different frequencies of PEMF in promoting the osteoarthritic cartilage regeneration of MSC-derived exosomes. The adipose tissue-derived MSCs (AMSCs) were extracted from the epididymal fat of healthy rats and further exposed to the PEMF at 1 mT amplitude and a frequency of 15, 45, and 75 Hz, respectively, in an incubator. The chondrocytes were treated with interlukin-1β (IL-1β) and the regenerative effect of co-culturing with PEMF-exposed AMSC-derived exosomes was assessed via Western blot, quantitative polymerase chain reaction, and ELISA assays. A rat model of osteoarthritis was established by anterior cruciate ligament transection (ACLT) surgery and received 4 times intra-articular injection of PEMF-exposed AMSC-derived exosomes once a week. After 8 weeks, the knee joint specimens of rats were collected for micro-computed tomography and histologic analyses. PEMF-exposed AMSC-derived exosomes could be endocytosed with IL-1β-induced chondrocytes. Compared with the AMSC-derived exosomes alone, the PEMF-exposed AMSC-derived exosomes substantially suppressed the inflammation and extracellular matrix degeneration of IL-1β-induced chondrocytes as shown by higher expression of transcripts and proteins of COL2A1, SOX9, and ACAN and lower expression of MMP13 and caspase-1. Of these, the 75-Hz PEMF presented a more significant inhibitive effect than the 15-Hz and 45-Hz PEMFs. Furthermore, the intra-articular injection of 75-Hz PEMF-exposed exosomes could obviously increase the number of tibial epiphyseal trabeculae, lead to a remarkable decrease in Osteoarthritis Research Society International score, and upregulate the COL2A1 and ACAN protein level of the degenerated cartilage. The present study demonstrated that PEMF stimulation could effectively promote the regeneration effects of AMSC-derived exosomes on osteoarthritic cartilage. Compared with other frequency parameters, the PEMF at a frequency of 75 Hz showed a superior positive effect on AMSC-derived exosomes in suppressing the IL-1β-induced chondrocyte inflammation and extracellular matrix catabolism, as well as the osteoarthritic cartilage degeneration.