StemCell Therapy

Introduction

As scholars have been studying tissue engineering more and more, oral bone regeneration which is of fundamental importance in the dentistry field has become a hot research topic.1 Mesenchymal stem cells (MSCs) are undifferentiated cells known for their self-renewal and differentiation properties, and they can secrete immunomodulatory factors, leading to the creation of a regenerative microenvironment, and trans-differentiate into cells of the different germ layers: mesoderm lineage cells, as well as ectoderm and endoderm lineage cells.2 The capacity of MSCs is useful for osteogenic differentiation and tissue regeneration.3 Some clinical studies have demonstrated that MSCs from different sources may have the ability to repair, replace, and regenerate cells, tissues, and bones.4 MSCs can be extracted from different tissues such as bone marrow, skeletal muscle, cartilage, dental organ, adipose tissue, synovium, and cardiac tissue.5 BMSCs were the first to be discovered.6 Bone is formed via endochondral and intramembranous ossification.7 MSCs play a vital role in bone formation. On the one hand, MSC-driven condensation occurs firstly, and then, MSCs differentiate into chondrocytes during the process of formation of growth plates, which are replaced by new bone in longitudinal-endochondral bone growth.8 On the other hand, MSCs can also directly differentiate into osteoblasts in bone formation such as skull, facial bones, and pelvis, generated by intramembranous ossification without a cartilaginous template.9,10

Transverse maxillary constriction often manifests a typical vertical skeletal pattern, with long anterior lower facial height, high palatal vault, low tongue posture, incompetent lip muscles, and mouth-breathing.11 Previous studies indicated that approximately 18% of mixed-dentition patients had a transverse maxillary constriction,12 which led to dentofacial deformities such as anterior deep overbite, posterior reverse overbite, and dental crowding. In general, the mid-palatal suture can be disrupted and separated by exerting a rapid transverse force on the maxillary dentition which surpasses the limit of orthodontic movement; continuous force increases cellular activity in the area and induces bone remodeling13 in a process called rapid maxillary expansion (RME). Since mid-palatal suture opening was first reported by Angell, RME has become a widely performed procedure by orthodontists. RME is also considered crucial for remedying maxillary constriction in children and growing adolescents, as skeletal component rigidity limits expansion extent and stability as the patient matures. Some orthodontists suggest that early treatment to correct transverse discrepancy may avoid future extractions.14 Of note, although the mid-palatal suture can be successfully opened, relapse of the posterior dentition width has been frequently reported;15,16 forces that induce relapse continue to act for up to six weeks after active expansion.17 A major reason for early relapse is inadequate bone formation in the suture. Consequently, a long retention period using a fixed retainer is often used to lessen the relapse. It was previously reported that the extent of relapse was related to the retention procedure after expansion, and thus a fixed retainer was required for at least two months.18 However, the discomfort caused by the considerable volume of a fixed retainer may reduce patient self-discipline to maintain the effectiveness of a previous RME, and similarly, the fixed retainer may increase the risk of caries due to accumulated dental plaque. Therefore, many RME studies have focused on different approaches to enhance new bone formation, strengthen post-treatment width, ensure enough stability, and shorten the retention period.1923

The pueraria plant is believed to be one of the earliest traditional herbs used in ancient Chinese medicine. Puerarin is a phytoestrogen first isolated from the pueraria root in the late 1950s and is one of the main isoflavone components in the root.24 In 2005, the pueraria plant was identified as the 6th most important food crop by the World Food and Agriculture Organization. The pharmacological activity of puerarin has been extensively investigated since its isolation, with activities including neuroprotective effects,25 vasodilatory activity,26 cardioprotective activity,27 anti-diabetic activity and the inhibition of diabetic complications,28 anti-Parkinsons disease activity,29 anti-Alzheimers disease activity,30 anti-osteoporotic activity,31 antioxidant activity,32 and others.24 Furthermore, evidence has suggested that puerarin dissolved in collagen matrix increases new bone formation in bone graft defect sites and may be used for bone grafting and bone regeneration after surgery.33,34 Therefore, it is reasonable to hypothesize that pueraria treatment may promote bone regeneration in the mid-palatal suture. As no reports on the puerarin stimulation of bone formation in the mid-palatal suture have been published, our objective was to investigate the effects of puerarin on osteogenesis in vitro and bone regeneration in vivo in the expanding mid-palatal suture and provide a theoretical foundation for its therapeutic effects toward RME and relapse prevention.

The study was complied with the ARRIVE guidelines and carried out in accordance with the UK Animals (Scientific Procedures) Act, 1986 and associated guidelines, EU Directive 2010/63/EU. The study was approved by the Animal Research Committee of School of Stomatology, Shandong University (Protocol No.: 20210121). All efforts were made to minimize the number of animals used and their suffering.

Rat bone marrow-derived mesenchymal stem cells (BMSCs) were accessed from bilateral femora and tibiae of two-week-old Wistar rats from the Laboratory Animal Center of Shandong University. Euthanized rats were soaked in and sterilized with 75% alcohol; bilateral femurs and tibiae were separated under aseptic conditions within 15 min to ensure the cell activity. After washing the long bones, the metaphyses were removed, and bone marrow was harvested out from the cavity with -minimum essential medium (-MEM; Hyclone, Logan, UT, USA), complemented with 15% fetal bovine serum (FBS; Biological Industries, Israel) and 1% penicillin/streptomycin (Hyclone; GEHealthcare Life Sciences, Logan, UT, USA). BMSCs were collected after suspension and cultured in the incubator in a humidified atmosphere of 95% air and 5% CO2 at 37 , the medium was renewed every 3 days. Once the cells reached 80%, they were rinsed with phosphate-buffered saline (PBS), digested with a 0.25% trypsin-EDTA solution (Thermo Fisher Scientific Inc) and sub-cultured with complete medium. BMSCs at passage 3 were used in subsequent experiments. Eventually, the expressions of cell surface molecular markers (CD 34, CD 44, CD 45, and CD 90) were analyzed by flow cytometer (Beckman Coulter, Franklin Lakes, NJ, USA) to identify the stem cell properties of the collected BMSCs.

To identify the multi-directional differentiation potential of BMSCs, they were induced by osteogenesis and adipogenesis. The cells in passage 3 were seeded in 6-well plates at a density of 1.0 105 cells per well and cultured to 90% confluence with complete medium, and then, the medium was changed to osteogenic inducing medium (-MEM containing 8% FBS, 50 g/mL ascorbic acid, 10 mM -glycerophosphate and 0.01 M dexamethasone) (Sigma-Aldrich) or adipogenic inducing medium (-MEM containing 8% FBS, 500 M 3-isobutyl-1-methylxanthine, 200 M indomethacin, 1 M dexamethasone and 10 g/mL insulin) (Sigma-Aldrich). After culturing for 21 days, BMSCs were fixed with 4% paraformaldehyde, stained with Oil Red O and Alizarin Red S (Cyagen Bio-Sciences, Guangzhou, China).

The Cell-counting Kit-8 (CCK-8; Dojindo Laboratories, Kumamoto, Japan) was used to determine the effect of puerarin on the proliferation of BMSCs. BMSCs were placed in 96-well plates with complete medium at a density of 5000 cells per well for 24 h. Next, the medium was replaced by complete medium supplemented with puerarin (GN10680; GlpBio, American) (Figure 1A) at different concentrations (0, 103, 104, 105, 106, 107 and 108 mol/L), five duplicate wells were set for each concentration group. 1, 3, 5 day(s) later, the medium was aspirated, and then 100 L of Cell-counting Kit-8 solution (-MEM and CCK-8 reagent mixing in a ratio of 9 to 1) was added into every tested well. Wells containing 100 L CCK-8 solution without seeding cells were used as blank control. The absorbance of samples was measured by a microplate reader (SPECTRAstar, Nano, BMG Labtech, Ortenberg, Germany) at 450 nm after incubation for 2 h at 37 in a darkroom.

Figure 1 Model of rapid maxillary expansion (RME) and three-dimensional reconstruction of the occlusal view of the rat maxilla. (A) Chemical Structure of Puerarin (C21H20O10). (B) Plaster model of rat maxillary. (C) Expansion appliance. (D) Inserted expansion appliance. (E) Bonded expansion appliance. (F) Rat maxillae after carefully dissected. (G) Rat head in the occlusal view, the vertical red line marking the occlusal position of the mid-coronal plane of the upper first molar, the horizontal red line marking the position of mid-palatal suture. (H) Rat head in the sagittal view, the red line marking the sagittal position of the mid-coronal plane of the upper first molar. (I) The distance of the mid-palatal suture in one of the rats in group 1 is 0.13mm. (J) The position and length of the ROI (2.0mm*1.0mm*0.8mm) in the coronal plane, horizontal plane, sagittal plane respectively. (K) 3D position view of ROI. (L) Location and plane of sectioning in the mid-palatal region.

To determine the ability of clone formation, BMSCs were seeded in 6-well plates at a density of 600 cells per well for 10 days, after fixing with 4% paraformaldehyde, cells were stained with crystal violet (Solarbio, Beijing, China). Cell colonies (clusters with 50 or more cells originated from the same cell) were counted to determine the ability of BMSCs to proliferate and form colonies.

The ALP activity assay is widely used to estimate the early osteogenesis ability of stem cells. BMSCs were plated in 6-well plates at a density of 1.0 105 cells per well and treated with osteogenic inducing medium containing different concentrations of puerarin (0, 104, 105, 106 and 107 mol/L). After 7 and 14 days of induction, cells were rinsed three times with PBS and solubilized in the lysis solution (ripa buffer and PMSF mixing in a ratio of 99 to 1) (Solarbio, Beijing, China) for 15 min on ice. Lysed the collected solution under ultrasound for 10 cycles (Bioruptor Pico, Diagenode, Belgium), and then, cell lysates were centrifuged at 12,000 g for 5 min at 4 . The supernatant was collected to obtain protein. Following the instructions of the manufacturer, an ALP activity assay kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, China) was used to measure the absorbance of the samples using a microplate reader at 520 nm. ALP activity was normalized to the respective total protein concentration detected by the bicinchoninic acid (BCA) protein assay kit (Solarbio, Beijing, China).

BMSCs were plated in 6-well plates at a density of 105 cells per well and treated with osteogenic inducing medium containing different concentrations of puerarin (0, 104, 105, 106 and 107 mol/L) for 21 days. After fixed with 4% paraformaldehyde for 30 min, cells were stained with Alizarin red S (pH 4.1, Sigma-Aldrich) for 15 min, the stained plates were scanned to evaluate mineralized matrix deposition. Then, 10% cetylpyridinium chloride (CPC; Solarbio, Beijing, China) was added to the stained plates to dissolve the mineral nodules. The absorbance of the solution used to quantify the mineral nodules was measured by a microplate reader at 562 nm.

BMSCs were cultured in osteogenic inducing medium containing different concentrations of puerarin (0, 105, 106 mol/L) for 7 and 14 days. According to the manufacturers instructions, the Evo M-MLV RT Kit with gDNA Clean for qPCR II (AG11711; Accurate Biology, Hunan, China) was used to isolate total mRNA and prepare cDNA. The SYBR Green Premix Pro Taq HS qPCR Kit (AG11701; Accurate Biology, Hunan, China) and a Roche Light Cycler 480 Sequence Detection System (Roche Diagnostics GmbH, Mannheim, Germany) were used to perform reverse transcriptase polymerase chain reaction (RT-PCR), and a reaction system of 10 L volume was adopted. Every RNA sample was tested in triplicate, and each experiment was repeated at least 3 times, the mRNA expression levels were calculated by the 2Ct method using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a control. The primer sequences used in the present study were as follows: ALP (+): 5-AGTGTGGCAGTGGTATTGTAGG-3 and 5-CACACACAAAGCACTCGGGG-3; SP7 (-): 5- GGTCCTGGCAACACTCCTAC-3 and 5-AAGAGGTGGGGTGCTGGATA-3; BSP (-): 5-AGCTGACCAGTTATGGCACC-3 and 5-TTCCCCATACTCAACCGTGC-3; OCN (+): 5-TGACAAAGCCTTCATGTCCAAG-3 and 5-GAAGCCAATGTGGTCCGCTA-3; GAPDH (+): 5- ACTCCCATTCTTCCACCTTT-3 and 5-CCCTGTTGCTGTAGCCATATT-3. The plus sign (+) indicates that the primers cross exon boundaries.

After culturing in osteogenic inducing medium containing different concentrations of puerarin (0 and 105 mol/L) for 14 days, BMSCs were lysed with RIPA lysis buffer containing 1% PMSF (Solarbio, Beijing, China). The total collected protein concentrations were quantified by a BCA protein assay kit. All protein samples (20g) were denatured and separated via 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and were transferred onto 0.45-m polyvinylidene difluoride membranes (PVDF; Millipore, Billerica, MA, USA). Afterwards, the membranes were blocked with 5% skimmed milk at room temperature for 1 h and incubated with primary antibodies that recognized -catenin (1:800; Cell Signaling Technology, Danvers, MA, USA), GAPDH, ALP, Runx2, Collagen I (Col I) (1:1000; Abcam, Cambridge, MA, USA) overnight at 4 . After washing in Tris-buffered saline with 0.1% Tween 20 (TBST), the membranes were incubated with a secondary antibody (Absin, Shanghai, China) solution at 37 for 1 h. Secondary antibodies were selected based on the source of primary antibodies. An enhanced chemiluminescent substrate kit (Millipore) and a chemical imaging system (Amersham Imager 600; GE Healthcare, Little Chalfont, UK) were used to detect immunoreactive proteins. GAPDH was used as internal reference.

The rats were pair-housed in standard plastic cages in a specific pathogen-free animal laboratory of School of Stomatology, Shandong University, under controlled temperature (22 1), humidity (55 10%), interior noise (below 60dB) and a 12-h light/dark cycle. They were provided with a powder diet and water ad libitum. All the animals were acclimated for 1 week before the experiment started. The general condition and weight of each rat were monitored daily during the experiment.

Eighteen 6-weeks-old male Wistar rats (mean weight 200~220 g) were adopted in the present research. The animals were randomly divided into three groups as follows: group 1, six control rats without any treatment; group 2, six rats received rapid maxillary expansion and saline solution (15mg/kg/day) containing 2% DMSO; group 3, six rats received rapid maxillary expansion and puerarin (15mg/kg/day) dissolved in 2% DMSO and then diluted with saline. Based on the width of the dental arch from the rat maxillary plaster model (Figure 1B), a 0.014-inch Australian wire (TP Original Premier Wire, TP Orthodontic Appliance Co. Ltd, Wuxi, China) was used to bend the expansion appliances with two helices and two arms (Figure 1C). Rats in groups 2 and 3 are anesthetized by an intramuscular injection of 3 mg/kg xylazine hydrochloride and 35mg/kg ketamine hydrochloride to ensure the smooth progress of the maxillary expansion surgery. After calibrating the expansion force between the two arms to 100 5g, the appliance was inserted into the bilateral first and second maxillary molars (Figure 1D) and the stability of the RME system was enhanced with the addition of light-cured adhesives (Gluma Comfort Bond, Heraeus Kulzer GmbH, Hanau, Germany) (Figure 1E). The injection solution of puerarin was freshly prepared by solubilizing in 2% dimethyl sulfoxide (DMSO) before diluted in saline, and it must be applied within 15 min in the case of puerarin precipitate. The injection sites were located in the space between the frontal periosteum and the maxillary suture, and a disposable sterile insulin syringe with a 29G, 0.33*13 mm needle (Kindly Medical Devices, Shanghai, China) was used to minimize tissue damage. On day 14 after installation, all animals were generally anesthetized and then perfused transcardially with 4% paraformaldehyde (pH 7.2~7.6) for fixing, and their maxillae were carefully dissected (Figure 1F) for micro-CT analyses and histological examinations.

The maxillae of the rats were scanned using high-resolution scan mode (Quantum GX2 micro-CT, PerkinElmer, American) at the condition of 90 kV and 88 A, the 72*72mm FOVs was chosen with an effective pixel size of 9.0 m. The digital image was analyzed with Materialises interactive medical image control system V20.0 (MIMICS V20.0) and its accompanying software 3-MATIC. We imported the scanned data from micro-CT into MIMICS to build a 3D model of rat and placed the maxillary bones in the same orientation by calibrating the red reference line on the figure (Figure 1G and H). The width of the mid-palatal suture was obtained by measuring the expanded distance at the level of the mid-coronal plane of the upper first molar (Figure 1I). Meanwhile, the region of interest (ROI) (2.0mm*1.0mm*0.8mm) builded through 3-MATIC included the mid-palatal suture and the bilateral bone, the position of the ROI was shifted to ensure that the intersection of the red dotted lines (Figure 1J) was in the center of the ROI (Figure 1K). The osteogenesis ability of puerarin during RME was investigated by measuring the changes of the bone volume in ROI.

The specimens were decalcified in 10% ethylenediaminetetraacetic acid/phosphate-buffered saline for 8 weeks, then dehydrated through the ethanol series, rendered transparent by xylene, embedded in paraffin wax. Serial sections with a thickness of 5 m were prepared through bilateral maxillary first molars on the coronal plane (Figure 1L). Hematoxylin and eosin (HE) staining and Masson staining for histologic observation were performed following manufacturers instruction.

Sections were dewaxed in xylene and rehydrated in graded ethanol baths, then enzyme-treated with 0.1% (w/v) trypsin at 37 for 10 min to antigen retrieval, blocked with 3% hydrogen peroxidase for 30 min to inhibit endogenous peroxidase activity, preincubated in normal goat serum for 35 min to blocked nonspecific binding. Next, we incubated rabbit polyclonal antibody (Abcam Inc., MA, USA) against BMP2 (working dilution, 1:200) and ALP (working dilution, 1:150) in humid chamber overnight. Subsequently, sections were rinsed in PBS, and the immune reaction was detected according to the 2-step DAB detection kit (Zhongshan Golden Bridge Biotechnology, Beijing, China). All sections were counterstained with hematoxylin for 3 min, followed by running water for 10 min. Under 400 magnification, the average optical density (AOD) value of the immunohistochemical images was analyzed by ImageJ (National Institutes of Health). The process was performed in five randomly selected visual fields per animal, and the average values were calculated by one person repeating at least three times.

All data were obtained from at least three replicates of each experiment. Statistical analyses were performed with GraphPad Prism 8 (GraphPad Software Inc., La Jolla, CA, USA) and Microsoft Excel 2020 (Microsoft Corporation, Redmond, WA, USA). A one-way or two-way analysis of variance (ANOVA) was performed to analyze statistical calculations. All the above results were shown as the means standard deviation. All data were considered statistically significant when P < 0.05.

Rat BMSCs were harvested, purified, and cultured through the whole bone marrow wall-adherence method in vitro. Generally, primary BMSCs exhibited colony growth after 3~5 days with a typical longspindlelike and a number of protruding formations (Figure 2A). After 3 or more passages in culture, they tended to be more morphologically heterogeneous (Figure 2B). Following 3 weeks of osteogenic and adipogenic induction, the formation of Alizarin Red mineralized nodules showed the osteogenic potential of BMSCs (Figure 2C), and the Oil Red O lipid droplets indicated their adipogenic potential (Figure 2D). Furthermore, flow cytometry analysis was performed to identify the phenotypic characteristics of these mesenchymal stem cells (MSC). The results showed that BMSCs had high expression of MSC-specific markers CD44 and CD90 but negative for CD34 and CD45 (Figure 2EH). Collectively, the above conclusions indicated that the isolated adherent cells were phenotypically and functionally equivalent to typical MSCs.

Figure 2 Cultivation and characterization of BMSCs. (A) Cell morphology of primary BMSCs. Scale bar: 100 m. (B) Cell morphology of passage 3 BMSCs. Scale bar: 100 m. (C) BMSCs were stained with Alizarin red S after osteogenic differentiation induction. Scale bar: 50 m. (D) BMSCs were stained with oil red O after adipogenic induction. Scale bar: 100 m. (EH) Analysis of BMSCs surface markers expression by flow cytometry. The high expression is on the right side of the central axis. The expression of CD34 and CD45 were negative, while CD90 and CD44 were highly expressed.

The results of the cell proliferation are analyzed by the CCK-8 assay (Figure 3A and B). On day 3, compared with the control group, proliferative capacity of BMSCs at the puerarin concentrations of 106 mol/L was significantly higher (P < 0.01), the 104, 105 and 107 mol/L group also showed a clear increase (P < 0.05), the 108 mol/L group showed a slight increase, but there was no statistically significant (P > 0.05). As time gone by, the trend of the effect of puerarin on proliferation of BMSCs became pronounced. Conversely, the 103 mol/L group markedly inhibited the proliferation of BMSCs (P < 0.0001). Considering the cytotoxic effects, 104, 105, 106 and 107 mol/L groups were chosen for the following assays. The colony formation assay showed that after culturing for 10 days, the cell colonies of the 106 mol/L group were obviously larger and more numerous (P < 0.01) than those of the control group (Figure 3CE).

Figure 3 Effects of puerarin on the proliferation of BMSCs. (A) The growth curves of puerarin-treated groups at different concentration were drawn according to the results of CCK-8 analysis. (B) CCK-8 analysis for the proliferation of BMSCs in various concentration of puerarin on day 3 and 5 (two-way analysis of variance). (C and D) Colony formation assay was performed to test the colony forming capacity of BMSCs. After 10 days, more and larger cell colonies were observed in the experimental group (D) than those in the control group (C). (E) The colony forming efficiency of 106 mol/L puerarin group (one-way analysis of variance). Scale bar: 100 m. The columns represent the means. Error bars represent standard deviations. *P< 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

This research measured the ALP activity level of BMSCs cultured with different concentrations of puerarin (0, 104, 105, 106 and 107 mol/) in two periods (Figure 4A). It was found that compared with the control group, ALP activity level at the various concentrations of puerarin measurably increased to different degrees (P < 0.05) on day 7 and day 14 with the similar trend; clearly, 106 mol/L group obtained the best effects. For the alizarin red S staining assay (Figure 4BE), the 106 mol/L group showed the strongest capacity of matrix mineralization (P < 0.01), more and larger calcified nodules were observed in the 105 and 106 mol/L groups. Based on the above measurements, we conclude that 106 mol/L is the optimal concentration for the proliferation and osteogenesis of BMSCs. Besides, it is worth noting that 105 mol/L has the same positive effect on BMSCs which is only slightly weaker than the optimal concentration, so the concentrations of 105 and 106 mol/L were used in the real-time PCR analysis to enhance the reliability of the experiment, and the concentrations of 106 were used in the Western blot analysis. The mRNA expression levels of the osteogenesis-related genes (ALP, SP7, BSP and OCN) and the protein expression levels of the osteogenesis-related proteins (Col I, -catenin, Runx2, and ALP) were evaluated to assess the osteogenic promotion effect of puerarin. Compared with the control group, the two puerarin-treated group significantly enhanced the expression of the above-mentioned genes on day 7 and day 14 (P < 0.05; Figure 5AD). Furthermore, compared to the control group, the protein expression levels of Col I, -catenin, ALP, Runx2 were showed an upregulated trend on day 14 (Figure 5E). These data indicated that puerarin might play a positive role in the osteogenic differentiation of BMSCs.

Figure 4 Effects of puerarin on ALP activity and mineralized nodule deposition of BMSCs. (A) ALP activity quantification of BMSCs stimulated with puerarin for 7 and 14 days (two-way analysis of variance). (B) Quantitative analysis of Alizarin red S staining of BMSCs stimulated with puerarin for 4 weeks (one-way analysis of variance). (CE) Alizarin red S staining of control group (C), 105 mol/L (D) and 106 mol/L (E) puerarin group. Scale bar: 200 m. The columns represent the means. Error bars represent standard deviations. *P < 0.05, **P < 0.01.

Figure 5 Effect of puerarin on the ALP (A), BSP (B), OCN (C), SP7 (D) expression of BMSCs at 7 and 14 days (two-way analysis of variance). The mRNA expression level of GAPDH was used as internal reference. The columns represent the means. Error bars represent standard deviations. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

The body weights decreased of the rats in group 2 and group 3 at day 1~5, due to the initial in adaptation to the maxillary expansion appliances, which were significantly different from the steady increase in group 1 (P < 0.05; Figure 6A). However, from day 6, the weight gradually gained among all rats with no significant differences. In addition, there is no significant difference in weight between group 2 and group 3 during the study (P > 0.05). The results showed that the rats recovered quickly from the surgery and were well tolerated to the experimental condition. Micro-CT analysis revealed that compared with group 1, the mid-palatal sutures of rats in groups 2 and 3 were expanded after expansion surgery at day 14 (P < 0.01; Figure 6B), indicating that the RME animal models were successfully established. However, there was no statistical significance (P > 0.05) between group 2 and 3 in terms of the expanded width of the mid-palatal suture. The data of bone volume in the fixed region was measured for evaluating new bone formation in the mid-palatal suture. Compared with group 1, the bone volume in groups 2 and 3 showed significantly reduce (P < 0.01; Figure 6C). Moreover, the bone volume in group 3 was higher than that in group 2 (P < 0.01), implied the application of puerarin had a positive effect on mid-palatal suture osteogenesis.

Figure 6 Animal weight and changes of mid-palatal suture response to the expansion force (n=6). (A) Changes of body weight during experimental period (two-way analysis of variance). (B) Width of the mid-palatal suture (one-way analysis of variance). (C) Bone volume of the mid-palatal suture (one-way analysis of variance). The columns represent the means. Error bars represent standard deviations. *P < 0.05, **P < 0.01, ***P < 0.001.

HE-stained (Figure 7AC) showed the mid-palatal suture in rat of group 1 is made up of a thin band cellular fibrous tissue in the middle and bilateral cartilage with chondrocytes covering the edges of palatal bones. After the mechanical stimulation, the width of the mid-palatal suture is significantly enlarged in response to external force, and two layers of secondary cartilage expand towards the reddish widened fibrous tissue following the same direction as the expansive force, concomitant with the chondrocytes proliferated and differentiated into hypertrophic chondrocytes. Masson staining (Figure 7DF) showed that the cartilage and the collagen fibers in the area of the expanded mid-palatal suture were stained blue, and more hypertrophic chondrocytes were found in group 3 compared with group 2, implying more active endochondral ossification was in progress in group 3.

Figure 7 Histological alterations and immunohistochemistry analyses in the mid-palatal sutures. (AC) HE staining showed the changes of the mid-palatal suture in histological sections. (DF) Masson staining showed the changes of the mid-palatal suture in histological sections. b, maxillary bone; c, cartilage; f, fibrous tissue; black arrow: the direction of stretch force; black triangle: the chondrocyte; black pentagram: the capillary; black dotted line: expanded region. Scale bar: 50 m. (GI) ALP was detected by immunohistochemistry analyses. (JL) BMP2 was detected by immunohistochemistry analyses. Yellow triangle: the positive signal. Scale bar: 20 m. (M and N) Quantification of the expression level of ALP and BMP2 (one-way analysis of variance). The columns represent the means. Error bars represent standard deviations. *P < 0.05, **P < 0.01, ***P < 0.001.

The positive expressions for osteogenic markers ALP (Figure 7GI) and BMP2 (Figure 7JL) were the brownish-yellow stained particles that were mainly observed in the osteoblasts, chondrocytes and fibrous tissue around the mid-palatal suture. Low expression level of ALP and BMP2 was detected in the mid-palatal suture of group 1 accompanied by the absence of few positive cells, while strong signals of them were observed around the expanded suture in group 2 and group 3 which possess the characteristics of big volume and abundant amount of the positive cells, implying active new bone formation in the mid-palatal suture region. Furthermore, compared with group 2, more intense expression was recognized in group 3 according to the higher AOD value (P < 0.01; Figure 7M and N).

Our data suggested that puerarin upregulated the proliferation and osteogenic differentiation of BMSCs. Also, the local administration of puerarin enhanced new bone formation in our RME rat model. RME is a distraction osteogenesis (DO) surgical technique that generates new bone between separated bone segments via the application of continuous and stable force. The procedure is advantageous in terms of low surgical trauma, no requirements for bone grafting, and peripheral soft tissue can be expanded at the same time. Since its first introduction in 1969,35 the DO technique has been widely used to enhance bone regeneration in orthopedic and oral/maxillofacial disorders.36 However, a limitation of RME is that newly formed immature bone tissue requires a prolonged consolidation period to mature, mineralize, and achieve desired distances, which may sometimes trigger oral complications or be often ignored by patients. To ensure its therapeutic efficacy, numerous methods have been investigated, including low-power laser therapy,19 LED (light-emitting diode) phototherapy,37 vitamin supplementation,20 isoquercitrin administration,21 sex steroids,22 curcumin and melatonin,23 and strontium ranelate.38

Based on the data from in vitro and in vivo studies, puerarin was effective in inhibiting bone resorption and improving bone structure. Previous studies showed puerarin decreased receptor activator of nuclear factor -B ligand (RANKL) expression and increased osteoprotegerin (OPG) expression to stimulate osteoblastic proliferation,39 which induced the upregulation of miR1553p,33 BMP2 expression and nitric oxide (NO) synthesis40 to promote cell differentiation and bone formation. Furthermore, puerarin can promote osteogenic differentiation which involved ERK1/2 and p38-MAPK pathway,41 ER, p38 MAPK, and Wnt/-catenin pathways,42 and PI3K/Akt pathway.43 Also, puerarin prevented osteoclastogenesis by inhibiting Akt activation in RAW264.7 cells44 and blocking monocyte chemotactic protein-1 (MCP-1) production.45 In our study, puerarin dose-dependently enhanced osteogenic differentiation and mineralization, and upregulated ALP, SP7, BSP and OCN mRNA levels, suggesting positive stimulatory effects on osteogenic differentiation. Moreover, increased ALP activity after treatment with puerarin was observed in other studies46 in agreement with our findings. ALP has important roles in osteoid formation and mineralization,46 therefore ALP activity is an early osteoblast differentiation marker; BSP is a phosphorylated glycoprotein mainly expressed in mineralized tissue such as bone, and was shown to be the main synthetic product of active osteoblasts;47 OCN is an important component in bone endocrinology and is secreted solely by osteoblasts;48 and SP7 is a critical regulator of osteoblast differentiation and bone formation and induces pre-osteoblast differentiation into fully functional osteoblasts.49 A lot of growth factors, hormones and proteins participate in osteoblast differentiation of MSCs. The Wnt/-catenin signaling pathway is known as one of the important and typical molecular cascades that regulate osteogenic throughout lifespan. Studies have shown that activation of Wnt/-catenin pathway promotes BMSC osteogenic differentiation and osteogenesis.50,51 The protein -catenin is the central target and an essential component of the Wnt/-catenin signaling pathway.52 -catenin also can preserve the stem state of BMSCs through activation of EZH2.53 Collagen type I (Col I), a protein abundantly found in the extracellular matrix, has been broadly shown to promote proliferation, survival, adhesion and osteogenesis in bone marrow MSCs.54 There is evidence that Col I promotes osteogenic differentiation of amniotic membrane-derived mesenchymal stromal cells in basal and induction media.55 It has been reported that growth on a remodeled Col I matrix by MMP13 stimulates osteogenic differentiation and self-healing of bone tissue via an MMP13/ITGA3/RUNX2 positive feedback loop.56 Runx2 is a key transcriptional modulator for osteoblast differentiation that plays a fundamental role in osteoblast maturation and homeostasis;57 it is considered as the master osteoblast-specific transcription factor even if many other factors coordinate bone remodeling. It is crucial in regulating bone differentiation of MSCs and is a key protein for bone formation.58,59 Due to the vital role of MSCs in osteogenic differentiation, we conclude from the above study that puerarin can promote bone regeneration in vitro. Furthermore, the optimal puerarin concentration for BMSC proliferation and osteogenesis was 106 mol/L.

Several animal models, including cynomolgus monkeys, miniature pigs, beagles, rabbits, and rats have been used to study bone regeneration; however, the rat model is widespread due to low costs, wide access to animals, simple model operation, and minimally invasive procedures. The fall-off rate for expansion devices during rat studies is relatively low, which in turn decreases experimental steps and ensures the accuracy of experimental results. This model is similar to clinical RME, using bilateral maxillary first molar as the anchorage teeth, and the mid-palatal suture separated accompanied by the buccal movement of the bilateral maxillary first molar. A previous study reported that the ideal time for RME was the prepubertal or pubertal period, as ongoing growth and development usually generated more stable orthopedic results,22 therefore 6-week-old rats were selected for this study. The experimental period was designed for 14 days. On the one hand, there would be a greater likelihood that the orthodontic force would decay to the point that it would not provide sufficient expansion of the mid-palatal suture after 2 weeks, thus, continuing the experiment may have less effect on the results. On the other hand, studies have shown that 7 and 10 days of RME already allow for an effective expansion of the mid-palatal suture.21,38 As it is medically unethical to systemically administer extrinsic medicines to growing healthy patients, we used local injections to minimize adverse systemic effects and support bone formation at regular time intervals in a particular area of rats in this study. Moreover, assessing direct responses to puerarin in mid-palatal suture bone formation may limit its systemic-administration due to the aforementioned multiple puerarin interactions with various organs or tissues. To the best of our knowledge, ours is the first study to investigate the effects of this locally administered traditional herb and observe no degenerative changes around injection sites.

In recent years, micro-computed tomography has rapidly gained recognition as a standard scanning and analytical tool for bone structures due to its ability to gather key bone structural parameters, and accurately visualize structures in three dimensions.60 In our study, the expanded distance of the mid-palatal suture was wider in groups 2 and 3 when compared with group 1, demonstrating a significant efficacy for RME in rats, in agreement with a previous study.21 However, we observed no significant differences between groups 2 and 3 in terms of the expanded width of the mid-palatal suture, probably because DO can be divided into three temporal phases: a latency period of 510 days, a distraction phase, and a consolidation phase. The mid-palatal suture was in the early stage of distraction at day 14, forming a central fibrous zone as the primitive callus was stretched; this phase was rich in chondrocyte-like cells, fibroblasts, and oval cells which were morphological intermediates between fibroblasts and chondrocytes.61,62 At this time, the puerarin effects on bone remodeling were at initial microscopic stages and were not yet reflected at the macroscopic level. Notably, a significant increase in bone volume was identified in group 3 in the expanded mid-palatal suture, suggesting accelerated new bone deposition and formation in response to puerarin.

Our immunohistochemical analyses showed that BMP2 and ALP expression increased in the expanded mid-palatal suture. BMPs are growth factors which belong to the transforming growth factor-superfamily; they induce endochondral bone formation63 and are involved in bone regeneration during osteoblast differentiation, and their increased expression enhances new bone formation.64 Similarly, ALP is a reliable biochemical marker of bone formation.65 The AOD value showed puerarin increased ALP and BMP2 expression levels during RME, thereby upregulating bone regeneration. Heterotopic ossification (HO) is one of the hot spots of research on post-traumatic complications,66,67 and it has been reported that elevated BMP2 is positively correlated with the occurrence of HO.68 It is noteworthy that though puerarin upregulates BMP2 level when it is used to stimulate osteogenesis in mid-palatal suture, we presume that HO is less likely to occur in the context of safe, physiological, controlled RME. The limitation of the study was that the precise osteogenic mechanism of puerarin towards BMSCs was not fully elucidated as RME is a complex process; the effect of puerarin on osteoblast differentiation is an area worthy of further exploration, therefore future research must elucidate more biological effects of puerarin on bone regeneration.

We demonstrated that puerarin promoted BMSCs proliferation and osteogenic differentiation in vitro and enhanced new bone regeneration in vivo. Our research may serve as an experimental paradigm for the appropriate utilization of puerarin in clinical studies to accelerate bone formation and prevent relapse for RME.

BMSCs, bone marrow-derived mesenchymal stem cells; RME, rapid maxillary expansion; CCK-8, cell-counting kit-8; ALP, Alkaline phosphatase; BSP, bone sialoprotein; OCN, osteocalcin; Micro-CT, micro-computed tomography; HE, hematoxylin and eosin; BMP2, bone morphogenetic protein 2; MSCs, mesenchymal stem cells; -MEM, -minimum essential medium; FBS, fetal bovine serum; PBS, phosphate-buffered saline; BCA, bicinchoninic acid; CPC, cetylpyridinium chloride; RT-PCR, reverse transcriptase polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Col I, Collagen I; DMSO, dimethyl sulfoxide; AOD, average optical density; DO, distraction osteogenesis; LED, light-emitting diode; RANKL, receptor activator of nuclear factor -B ligand; OPG, osteoprotegerin; MCP-1, monocyte chemotactic protein-1; NO, nitric oxide.

This work was supported by the Natural Science Foundation of Shandong Province, China (No. ZR2021QH340).

The authors report no conflicts of interest in this work.

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Effect of Puerarin on New Bone Formation In Vivo | DDDT - Dove Medical Press

image:Autologous intestinal organoids of ulcerative colitis patients are delivered for transplantation by GI endoscopists. view more

Credit: Department of Gastroenterology and Hepatology, TMDU

Tokyo Medical and Dental University (TMDU) research team announced on July 7 that it has succeeded in the worlds first clinical transplantation of a mini organ (also called Organoid) into a patient with Ulcerative Colitis (UC). UC causes inflammation and ulcers (sores) in your digestive tract. It can be debilitating and can sometimes lead to life-threatening complications. UC belongs to a group of conditions called Inflammatory Bowel Disease (IBD). The number of patients is increasing in Japan and in the world is estimated to be about 220,000 and 5,000,000. The common treatment is to suppress inflammation with drugs, but in severe cases, the entire colon may be removed.

Dr. Mamoru Watanabe, vice president and distinguished professor of Tokyo Medical & Dental University said, If our first-in-human research using organoids transplantation yields good results, we expect that the development of organoid medicine for intractable diseases of the digestive tract such as Crohn's disease will progress.

Dr. Ryuichi Okamoto, a professor of the Department of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences said, We embarked on the path of developing new methods for treating intractable diseases. This treatment should establish the efficacy and safety as soon as possible and deliver to the patients. If the team's effort is successful, the mucous membrane may regenerate and lead to a radical cure of UC.

The clinical research started with collecting from the patients vicinity of a healthy colonic mucosa and culturing them for about one month to form spherical organoids with a diameter of about 0.1 to 0.2 mm. On July 5, an organoid was transplanted into the colon of the same patient using a colonoscopy. The patient did well and was discharged July 6.

In previous experiments using mice models, the team confirmed that the cells were cultured in organoids and then transplanted, the mucous membranes regenerated in about a month and the clinical course improved, while the stem cells alone did not transplant because they were not able to culture in vitro.

In this clinical study, since the patient's own cells are used, there is an advantage that transplant rejection does not occur. In addition, since colonoscopy is used for collection and transplantation, there is no need for laparotomy, and the treatment can be performed in a minimally invasive method.

After this transplantation, medical examination will be conducted at the time after 4 weeks and 8 weeks. The patient will be monitored for up to a year to verify safety and efficacy. A further organoids transplantation is to be performed for up to eight patients.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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The Tokyo Medical and Dental University (TMDU) team succeeded with the world's first Mini Organ transplantation to a patient with Ulcerative Colitis...

DUBLIN--(BUSINESS WIRE)--The "Global Regenerative Medicine Partnering Terms and Agreements 2015 to 2022" report has been added to ResearchAndMarkets.com's offering.

This report is intended to provide the reader with an in-depth understanding and access to Regenerative Medicine trends and structure of deals entered into by leading companies worldwide.

Regenerative Medicine Partnering Terms and Agreements includes:

In Global Regenerative Medicine Partnering Terms and Agreements 2015-2022, the available deals are listed by:

Each deal title links via Weblink to an online version of the deal record and where available, the contract document, providing easy access to each contract document on demand.

The Global Regenerative Medicine Partnering terms and Agreements 2015-2022 report provides comprehensive access to available deals and contract documents for over 1600 Regenerative Medicine deals.

Analyzing actual contract agreements allows assessment of the following:

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/pu1ymr

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Regenerative Medicine Partnering 2015 to 2022: Terms and Agreements Entered Into by the Leading Companies Worldwide - ResearchAndMarkets.com -...

A lot of people are intrigued byregenerative medicine and have heard promising information about the incredible power it has to promote healing. But theres also some confusion about what it really does and how it works.

So let's break down how and why we use these innovative therapies from head to toe and most importantly the benefits that patients see from them.

Headaches and Upper Neck Pain

Cervicogenicheadaches result from a neck issue and cause pain right below the junction of the head and neck in the cervical facet joints that allow you to turn your head side to side or forward to backwards. You may be dealing with this pain as a result of a traumatic injury, or because youre aggravated by repetitive motions like looking down and texting too much, watching TV in a poor position or having a desk set up that isnt ergonomic. Arthritis can exacerbate this problem, too.

When more traditional measures like physical therapy and massage therapy dont help, regenerative medicine can come into play. First, we usually try platelet-rich plasma (PRP) therapy, which is concentrated platelet-rich plasma protein that comes from your blood after we run it through a centrifuge to remove the red blood cells. Injecting PRP into the cervical facet joints can provide relief of acute and chronic neck pain by promoting the bodys natural healing potential. The reduction of pain combined with healing promotion can allow improvements in motion as well.

Stem cell therapy is another option. We harvest bone marrow from the pelvis and break it down to get stem cells and platelets. When we inject this into the problem area, it not only adds stem cells but also attracts more stem cells in your body at a greater rate speeding up recovery.

Both procedures change pathology and promote healing. Results can be long-term unless you injure or damage the tissue again and they can be dramaticstaving off surgery or providing a solution when surgery isnt an option.

Shoulder Pain

This most commonly presents as a rotator cuff tear and when that happens you have three options. Physical therapy helps most people get better but when it doesnt, regenerative medicine is an option if the tear affects 75 percent or less of the shoulder. If the tear is too extreme, surgery is needed.

Platelet rich plasma or PRP is the most commonly used regenerative medicine option for this injury. Its a non-operative solution that utilizes the bodys natural healing process. PRP therapy is a concentration of the patients own blood plasma injected into damaged ligaments, tendons, and joints to promote tissue repair and accelerate healing. It is rich in growth and healing factors and on average, an injured patient can get back to a pain-free life in four to six weeks.

This is a great option for shoulder injuries because most people are looking to avoid shoulder surgery given the risks and recovery.

Back Pain

Lowerback pain is the No. 1 reason people come to see me for regenerative treatment options, but this can be used to treat upper and mid-back pain too.

Regenerative medicine can help with facet joint issues, disc related pain, degeneration, a tear in disc space or irritated nerves (which can be a result of stenosis, nerve injury, surgery, etc.).

Platelet-rich plasma (PRP) therapy and stem cell therapy are both options to treat these conditions. The one we choose generally depends on individual factors with patients and their pain. The wonderful news is 100 percent improvement is possible but I should stress these therapies dont work well in the most severe cases, which likely still require surgery.

Hip Pain

The most typical cause of this pain is osteoarthritis in thehip joint but labral tears are common, too, especially among athletes.The type of treatment we opt for in the case of hip arthritis depends on how much narrowing of the joint is at play. Our top options include platelet-rich plasma (PRP) therapy and stem cell therapy.

Another option we havent yet discussed is lipoaspirate prolotherapy or adipose-derived stem cell therapy. These are also injections like PRP and stem cell therapybut they involve micro fragmented fat. We take fat from the belly and break it down to a thin paste and place it in a joint to provide cushioning and start the healing cycle. This procedure can be used for any joint hip, knee, shoulder or ankle.

Knee Pain

This is the second most common cause of pain that brings people to me for treatment (after lower back pain). The most typical triggers are arthritis but we also see a lot of meniscus and ACL tears too. PRP therapy, stem cell therapy and lipoaspirate prolotherapy are all options for this joint. But heres what you need to know withknee pain, because I know it can be concerning when it happens it is absolutely possible to heal this injury and get back to a place where you can limit and manage the problems.

Regenerative medicine makes that possible. Plenty of people come in with a meniscus tear and have been told they need surgery. Instead, we treat the tear with one of these options and have seen up to 100 percent relief. Many patients never end up in an OR, which is the goal.

It happens most often when the damage isnt too severe which is all the more reason to seek advice and help early in your pain cycle rather than waiting too long.

Ankle Pain

Treatingankle pain can be a bit trickier than other sources because we need to make sure ligaments of the ankle are intact. We can use regenerative medicine to treat both the ankle joint and the ligaments around it depending on the problem, which is generally caused by arthritis or an ankle injury maybe from rolling it.

Treatment options include PRP therapy and stem cell therapy. We have the option of using lipoaspirate prolotherapy as well when were targeting the ankle joint. One thing I havent mentioned previously is that sometimes we tap into more than one healing treatment. Its not unusual that we combine regenerative medicine therapies to accelerate healing.

Although we expect to complete the treatment one time, there are times when we also repeat the procedure to extend the benefit duration to include other nearby structures, or patients that request the procedure be repeated to continue avoiding surgery.

Regenerative medicinewhen done right, by a professionaltruly does have the ability to help you from head to toe and get you "back" to a pain-free, healthy life.

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Pain Relief Treatments: The Benefits of Regenerative Medicine From Head to Toe - 30Seconds.com

The Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) updated its Guidance Agenda in June 2022,1which provides that the agency plans to issue 18 guidance documents in 2022, including eight guidance documents on tissues and advanced therapies. In this alert, we highlight some key considerations from three draft guidance documents on human gene therapy products that incorporate gene editing (GE) components, chimeric antigen receptor (CAR) T cell products, and regenerative medicine therapies that can benefit biopharmaceutical developers and sponsors. Recognizing the challenges of developing such complex, multi-component biologic drug products, including unanticipated risks associated with on-target and off-target activities, these draft guidance documents describe the FDA's recommendations for preclinical and clinical testing, chemistry, manufacturing, and controls (CMC), as well as information that should be included in investigational new drug (IND) applications to ensure proper identity, potency/strength, quality, and purity of the investigational drug products. FDA recommends sponsors of such complex products to communicate with the Office of Tissues and Advanced Therapies (OTAT) in CBER early in product development before submission of an IND, to discuss the product-specific considerations in preparation for transitioning to the clinical phase.

FDA expects detailed information and data IND applications before sponsors can transition to clinical testing. We recommend biopharmaceutical developers and sponsors review the applicable FDA draft guidance documents early in their product development process to identify these needs. Work closely with both FDA regulatory counsel and intellectual property/patent counsel to ensure there is sufficient data to support an IND application, including adequate testing and quality control measures, and that CMC, preclinical, and clinical development plans are coordinated with intellectual property and patent strategies to ensure robust protection of their intellectual property and to maximize the benefits of their patents and FDA regulatory exclusivities. We also encourage interested persons to submit comments to shape the policies proposed in FDA's draft guidance documents prior to finalization.

Draft Guidance for Industry: Human Gene Therapy Products Incorporating Genome Editing2

Draft Guidance for Industry: Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products3

Draft Guidance for Industry: Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies4

Stakeholders have until September 14, 2022, to submit comments to this draft guidance to ensure they are considered by FDA before finalization of the guidance.

For More Information

For questions regarding FDA strategy, approval, and regulatory compliance, please contact any member of Wilson Sonsini'sFDA regulatory, healthcare, and consumer productspractice. For questions regarding intellectual property and patent counseling, please contact any member of Wilson Sonsini'spatents and innovationspractice.

Andrea Chamblee,Paul Gadiock, andEva Yincontributed to the preparation of this Wilson Sonsini Alert.

[1] FDA, Guidance Agenda: Guidance Documents CBER is Planning to Publish During Calendar Year 2022 (Updated June 2022), available at https://www.fda.gov/media/120341/download.

[2] FDA, Draft Guidance for Industry: Human Gene Therapy Products Incorporating Genome Editing (March 2022), available at https://www.fda.gov/media/156894/download.

[3] FDA, Draft Guidance for Industry: Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products, available at https://www.fda.gov/media/156896/download.

[4] FDA, Draft Guidance for Industry: Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies (June 2022), available at https://www.fda.gov/media/159237/download.

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FDA Issues Draft Guidance to Facilitate Development of Human Gene Therapy, CAR T Cell, and Regenerative Medicine Products - Wilson Sonsini Goodrich...

image:The ARDD Meeting 2022 will be hosted on August 29 - September 2, 2022 view more

Credit: Insilico Medicine Hong Kong Limited

August 18, 2022 Marco Quarta, Ph.D., will present the latest research on the topic From Single Cell AI-enabled Discovery of Cellular Senescence to Targeted Senolytic Drug Development at the worlds largest annual Aging Research and Drug Discovery conference (9th ARDD). Dr. Quarta is the CEO and Co-founder at Rubedo Life Sciences.

Marco co-founded and leads Rubedo Life Sciences driving its mission to develop treatments for age-related diseases and extend healthspan by selectively targeting pathological cells involved in the biological aging process. As a scientist, he earned a Masters degree in Biotechnology, a PhD in Neuroscience, and post-doctoral training in Aging and Stem Cells Biology in the lab of his mentor Prof. Thomas Rando at Stanford University School of Medicine. He then directed at Stanford/VA Hospital Palo Alto a research team focused on translational medical research in the fields of aging and regenerative medicine. He is backed by over 20 years of research with a track record of scientific publications in top tier journals. Marco is an inventor and entrepreneur, he co-founded and led the international biotech umbrella organization Young European Biotech Network (YEBN), and later joined the European Federation of Biotechnology (EFB) executive board.

Marco Quarta founded and led the biotech company WetWare Concepts in Europe. In California, with the Stanford colleague Prof. Vittorio Sebastiano he also co-founded Turn Biotechnologies based on their work on epigenetic reprogramming of cellular aging, where he served as CSO and he is a Board Director. Quarta sits on the advisory board of the California Institute for Regenerative Medicine (CIRM) Calpoly program in regenerative medicine. He is in the advisory and research board at the Center for Healthcare Innovation (CHI). He is a member of the Paul F Glenn Center for the Biology of Aging Studies at Stanford University. Quarta keeps fostering and championing high standards of compliance, ethics and patient safety in the development of innovative translational therapeutics, putting patients and society at the center of all actions.

The conference proceedings of the ARDD are commonly published in peer-reviewed journals with the talks openly available at http://www.agingpharma.org. Please review the conference proceedings for 2019, 2020 and 2021https://www.aging-us.com/article/203859/text .

Aging is emerging as a druggable condition with multiple pharmaceuticals able to alter the pace of aging in model organisms. The ARDD brings together all levels of the field to discuss the most pressing obstacles in our attempt to find efficacious interventions and molecules to target aging. The 2022 conference is the best yet with top level speakers from around the globe. Im extremely excited to be able to meet them in person at the University of Copenhagen in late summer. said Morten Scheibye-Knudsen, MD, Ph.D., University of Copenhagen.

Aging research is growing faster than ever on both academia and industry fronts. The ARDD meeting unites experts from different fields and backgrounds, sharing with us their latest groundbreaking research and developments. Our last ARDD meeting took place both offline and online, and it was a great success. I am particularly excited that being a part of the ARDD2022 meeting will provide an amazing opportunity for young scientists presenting their own work as well as meeting the experts in the field. said Daniela Bakula, Ph.D., University of Copenhagen.

Many credible biopharmaceutical companies are now prioritized aging research for early-stage discovery or therapeutic pipeline development. It is only logical to prioritize therapeutic targets that are important in both aging and age-associated diseases. The patient benefits either way. The best place to learn about these targets is ARDD, which we organize for nine years in a row. This conference is now the largest in the field and is not to be missed, said Alex Zhavoronkov, Ph.D., founder and CEO of Insilico Medicine and Deep Longevity.

Building on the success of the ARDD conferences, the organizers developed the Longevity Medicine course series with some of the courses offered free of charge at Longevity.Degree covered in the recent Lanced Healthy Longevity paper titled Longevity medicine: upskilling the physicians of tomorrow.

About Aging Research for Drug Discovery Conference

At ARDD, leaders in the aging, longevity, and drug discovery field will describe the latest progress in the molecular, cellular and organismal basis of aging and the search for interventions. Furthermore, the meeting will include opinion leaders in AI to discuss the latest advances of this technology in the biopharmaceutical sector and how this can be applied to interventions. Notably, this year we are expanding with a workshop specifically for physicians where the leading-edge knowledge of clinical interventions for healthy longevity will be described. ARRD intends to bridge clinical, academic and commercial research and foster collaborations that will result in practical solutions to one of humanity's most challenging problems: aging. Our quest? To extend the healthy lifespan of everyone on the planet.

About Scheibye-Knudsen Lab

In the Scheibye-Knudsen lab we use in silico, in vitro and in vivo models to understand the cellular and organismal consequences of DNA damage with the aim of developing interventions. We have discovered that DNA damage leads to changes in certain metabolites and that replenishment of these molecules may alter the rate of aging in model organisms. These findings suggest that normal aging and age-associated diseases may be malleable to similar interventions. The hope is to develop interventions that will allow everyone to live healthier, happier and more productive lives.

About Deep Longevity

Deep Longevity has been acquired by Edurance RP (SEHK:0575.HK), a publicly-traded company. Deep Longevity is developing explainable artificial intelligence systems to track the rate of aging at the molecular, cellular, tissue, organ, system, physiological, and psychological levels. It is also developing systems for the emerging field of longevity medicine enabling physicians to make better decisions on the interventions that may slow down, or reverse the aging processes. Deep Longevity developed Longevity as a Service (LaaS) solution to integrate multiple deep biomarkers of aging dubbed "deep aging clocks" to provide a universal multifactorial measure of human biological age. Originally incubated by Insilico Medicine, Deep Longevity started its independent journey in 2020 after securing a round of funding from the most credible venture capitalists specializing in biotechnology, longevity, and artificial intelligence. ETP Ventures, Human Longevity and Performance Impact Venture Fund, BOLD Capital Partners, Longevity Vision Fund, LongeVC, co-founder of Oculus, Michael Antonov, and other expert AI and biotechnology investors supported the company. Deep Longevity established a research partnership with one of the most prominent longevity organizations, Human Longevity, Inc. to provide a range of aging clocks to the network of advanced physicians and researchers. https://longevity.ai/

About Endurance RP (SEHK:0575.HK)

Endurance RP is a diversified investment group based in Hong Kong currently holding various corporate and strategic investments focusing on the healthcare, wellness and life sciences sectors. The Group has a strong track record of investments and has returned approximately US$298 million to shareholders in the 21 years of financial reporting since its initial public offering. https://www.endurancerp.com/

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Marco Quarta to present at the 9th Aging Research & Drug Discovery Meeting 2022 - EurekAlert

With age, it is common joint degeneration, especially of the hips and knees, which support the greatest load in our day to day life and commonly develop which is known as osteoarthritis, This deterioration of articular cartilage causes pain, stiffness, and loss of function, Therefore, it may represent a significant reduction in the quality of life of those who suffer from it. There is no treatment capable of curing osteoarthritis, but therapeutic avenues have emerged in recent years to reduce its symptoms, slow its development, and achieve an improvement in the patients quality of life.

it is a matter loss Treatment with plasma and stem cells rich in growth factorsApplied to prevent the progression of osteoarthritis, especially in large load-bearing joints. But its benefits go even further, explains the doctor. Jesus Villa y RicoHead of the Orthopedic Surgery and Traumatology Service at the Ruber Juan Bravo Hospital Complex in Madrid. These treatments also promote cartilage repair and reduce typical symptoms of osteoarthritis, including synovial swelling, effusion, deformity, pain or loss of motion.

There are many patients who are benefiting from advances in regenerative medicine in areas such as aesthetic medicine, ophthalmology or dentistry, but also in traumatology. It finds its use not only in reducing recovery time in bone, muscle and tendon injuries, but in the treatment of cases of disabling osteoarthritis or where conservative treatments are not sufficient.

It has no side effects or risk of rejection or intolerance, because the plasma comes from the patients own blood

Dr. Jesus Villa y Rico in Madrid, Ruber Juan Bravo Hospital

Platelet-rich plasma from the patients own blood is able to promote the regeneration of tissues damaged by osteoarthritis, thanks to the proteins and substances it contains. Stem cell treatments also allow the regeneration of these tissues. Growth factors produce biological effects such as cell proliferation and differentiation, the generation of blood vessels and the migration of cells to sites where regeneration is necessary, explains Dr. Villa. No exogenous agent can mediate all of these processes so effectively.

Treatment is carried out under medical prescription, in a sterile environment and with local anesthesia. For its application, blood is first taken from the patient, then it is processed and part of the plasma rich in growth factors is infiltrated into the area to be treated. This process may take 25 to 40 minutes, says the traumatologist.

With regard to the number of infiltrates, the protocol varies depending on the pathology. The Head of the Orthopedic Surgery and Traumatology Service of the Ruber Juan Bravo Hospital Complex in Madrid specifies that, In the specific case of joint pathologyWhat happens most often, is done three sessions for three consecutive weeks, with a refresher session after six months or one year if growth is favourable. Infiltration does not mean a period of recovery, so that the patient can lead a normal life from the very first moment.

The main benefit of this type of treatment is improvement in symptoms, namely reduction of pain and swelling. In case of tendon and muscle injuries, it has been proven that it accelerates healing. Too No side effects or risk of rejection or intolerance, because the plasma comes from the patients own blood, Dr. Villa says. This treatment is contraindicated only in case of local infections, neoplastic processes, and certain blood diseases, he explains.

In the specific case of stem cell treatment, infiltration represents an alternative to reconstructive surgery for chronic tendinopathies, acute tendon tears, chronic tendon tears and ligament tears, and osteonecrosis. In ligament surgery, such as the anterior cruciate ligament of the knee, exceptional results have also been obtained. in case of muscle injuryMore important than the reduction in recovery time is the use of plasma rich in growth factors. Allows recovery without the formation of fibrous tissue, experts say. It is also used in adjuvant treatment of osteochondral injuries in favor of the regenerative process of fibrocartilage, as well as in patellar tendon pathology, acute or chronic tendinitis, and ligamentous injuries.

Health

A holistic approach about our health is essential for achieving complete well-being and the highest quality of life. Its not about something organic and isolated that can []

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Osteoarthritis In The Hip Or Knee? Regenerative Medicine Revolutionizes Your Treatment - Nation World News

3D Systems Inc.

New 3D Systems Medical Advisory Board Members

Dr. Toby Cosgrove & Dr. Bon Ku

ROCK HILL, S.C., Aug. 18, 2022 (GLOBE NEWSWIRE) -- 3D Systems (NYSE:DDD) today announced the appointment of Dr. Toby Cosgrove, former president & chief executive officer of the Cleveland Clinic, and Dr. Bon Ku, director of the Health Design Lab at Thomas Jefferson University, as the fourth and fifth members of the companys recently established Medical Advisory Board (MAB). Dr. Cosgrove and Dr. Ku will join former Health & Human Services Secretary Alex Azar, Dr. Stephen K. Klasko, and former U.S. Secretary of Veterans Affairs David J. Shulkin as members of the advisory board. The Boards primary mission is to provide strategic input, guidance, and recommendations for the companys expanding efforts in regenerative medicine.

Dr. Cosgrove has distinguished himself as a leader of one of the worlds most recognized healthcare institutions, a renowned medical practitioner, and as a forward-looking healthcare innovator. Having been affiliated with the Cleveland Clinic healthcare system for nearly 50 years, Dr. Cosgrove served as President and Chief Executive Officer from 2004 to 2017 and is currently an Executive Advisor to the Clinic. As President and CEO, Dr. Cosgrove oversaw a $6 billion annual revenue institution comprised of the Cleveland Clinic, over 20 Ohio-based hospitals, family health centers, and surgical facilities, as well as Cleveland Clinic affiliates in other U.S. states and internationally. During Dr. Cosgroves tenure leading the Cleveland Clinic, it was ranked among the top three hospitals in America by U.S. News and World Report, and he championed a broad range of initiatives to improve clinical outcomes, increase patient satisfaction, and focus the Clinics delivery of health care services around specific organ systems and diseases.

Prior to serving as the Cleveland Clinics top executive, Dr. Cosgrove was a cardiac surgeon at the Clinic and served as Chairman of its Department of Thoracic and Cardiovascular Surgery from 1989 to 2004. He has performed more than 22,000 operations over the course of his career and is widely regarded as a pioneer in the field of advanced surgical techniques. Deeply committed to medical innovation and to applying new technologies for the benefit of patients, Dr. Cosgrove has over 30 patents filed for new medical and clinical products used in surgical environments.

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Dr. Bon Ku has enjoyed a distinguished career as both a practicing medical clinician and as a visionary proponent of using technology-based innovations to solve pressing healthcare challenges. Dr. Ku is the Marta and Robert Adelson Professor of Medicine and Design at Thomas Jefferson University as well as an emergency physician at the Universitys Sidney Kimmel Medical College.

Dr. Ku is widely regarded as an authority on accelerating healthcare innovation through the use of modern technological tools such as virtualization, digital modeling, prototyping, and additive manufacturing. He is the co-founder and Director of Thomas Jefferson Universitys Health Design Lab, a unique institution that works with medical students, researchers, and physicians to develop new medical devices and innovative design concepts for the healthcare sector. The Health Design Lab led by Dr. Ku features a clinical 3D printing and bioprinting lab and is home to the JeffSolves MedTech initiative, which serves as a center for the incubation and commercialization of new medical technologies. Dr. Ku is also the author of numerous peer-reviewed publications focusing on the application of 3D-printed medical devices and digital models to improve surgical outcomes, optimize treatments, and make advancements in personalized medicine.

Commenting on the appointments of Drs. Cosgrove and Ku, 3D Systems President and CEO, Dr. Jeffrey Graves stated, We are exceptionally pleased to welcome Dr. Cosgrove and Dr. Ku to our Medical Advisory Board. These two professionals have impeccable track records of combining hands-on medical practice experience with a clear passion for utilizing innovative approaches and modern technology to transform healthcare outcomes. Both Dr. Cosgrove and Dr. Ku will be uniquely positioned to advise 3D Systems as we build a world-class regenerative medicine business and pursue 3D printing-based advancements in areas such as accelerated pharmaceutical development, human tissue and organ printing, medical device innovation, and personalized medicine.

Forward-Looking StatementsCertain statements made in this release that are not statements of historical or current facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, performance or achievements of the company to be materially different from historical results or from any future results or projections expressed or implied by such forward-looking statements. In many cases, forward-looking statements can be identified by terms such as "believes," "belief," "expects," "may," "will," "estimates," "intends," "anticipates" or "plans" or the negative of these terms or other comparable terminology. Forward-looking statements are based upon managements beliefs, assumptions, and current expectations and may include comments as to the companys beliefs and expectations as to future events and trends affecting its business and are necessarily subject to uncertainties, many of which are outside the control of the company. The factors described under the headings "Forward-Looking Statements" and "Risk Factors" in the companys periodic filings with the Securities and Exchange Commission, as well as other factors, could cause actual results to differ materially from those reflected or predicted in forward-looking statements. Although management believes that the expectations reflected in the forward-looking statements are reasonable, forward-looking statements are not, and should not be relied upon as a guarantee of future performance or results, nor will they necessarily prove to be accurate indications of the times at which such performance or results will be achieved. The forward-looking statements included are made only as of the date of the statement. 3D Systems undertakes no obligation to update or revise any forward-looking statements made by management or on its behalf, whether as a result of future developments, subsequent events or circumstances or otherwise, except as required by law.

About 3D Systems More than 35 years ago, 3D Systems brought the innovation of 3D printing to the manufacturing industry. Today, as the leading additive manufacturing solutions partner, we bring innovation, performance, and reliability to every interaction - empowering our customers to create products and business models never before possible. Thanks to our unique offering of hardware, software, materials, and services, each application-specific solution is powered by the expertise of our application engineers who collaborate with customers to transform how they deliver their products and services. 3D Systems solutions address a variety of advanced applications in healthcare and industrial markets such as medical and dental, aerospace & defense, automotive, and durable goods. More information on the company is available at http://www.3dsystems.com.

Investor Contact: investor.relations@3dsystems.comMedia Contact: press@3dsystems.com

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/2b14f06b-98f9-4c66-8c02-b57375cab66d

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3D Systems Announces Appointment of Dr. Toby Cosgrove and Dr. Bon Ku as Members of its Medical Advisory Board - Yahoo Finance

The remarkable power of stem cells - which can be programmed to become almost any type of cell in the body - means they are key to many scientific studies.

Increasingly, they are also being used for new cell-based therapies to treat a range of diseases.

While originally we could only get stem cells from embryos, now we can derive them from a range of adult tissues, including skin or blood, using Nobel Prize-winning technology.

But Cambridge researchers have found DNA damage caused by factors such as ultraviolet radiation affected 72 per cent of the stem cell lines they studied that had been derived from human skin cells. This has important implications for research and medicine.

Prof Serena Nik-Zainal, from the Department of Medical Genetics at the University of Cambridge, said: Almost three-quarters of the cell lines had UV damage. Some samples had an enormous amount of mutations sometimes more than we find in tumours. We were all hugely surprised to learn this, given that most of these lines were derived from skin biopsies of healthy people.

Induced pluripotent stem cells (iPSCs), as those derived from other cell types or tissues are known, hold huge potential for tackling diseases, including rare conditions.

It is even suggested that iPSCs programmed to grow into nerve cells could be used to replace those lost to neurodegeneration in diseases such as Parkinsons.

The new research, published in Nature Genetics, represents the largest genetic study to date of iPSCs to date.

Dr Foad Rouhani, who carried out the work while at the University of Cambridge and the Wellcome Sanger Institute, said: We noticed that some of the iPS cells that we were generating looked really different from each other, even when they were derived from the same patient and derived in the same experiment.

The most striking thing was that pairs of iPS cells would have a vastly different genetic landscape one line would have minimal damage and the other would have a level of mutations more commonly seen in tumours.

One possible reason for this could be that a cell on the surface of the skin is likely to have greater exposure to sunlight than a cell below the surface and therefore eventually may lead to iPS cells with greater levels of genomic damage.

[Read more: Evidence of new causes of cancer uncovered as genomic data of 12,000 NHS patients is studied by University of Cambridge researchers]

DNA comprises three billion pairs of nucleotides - molecules represented by the letters A, C, G and T.

Damage from sources such as ultraviolet radiation or smoking leads to mutations, meaning a letter C might change to T, for example.

Studying the mutational fingerprints on our DNA can reveal what is responsible for the damage.

An accumulation of mutations can have a profound effect on cell function and in some cases lead to tumours.

Using whole genome sequencing, the researchers inspected the entire DNA of stem cell lines from different sources, including the HipSci cohort at the Wellcome Sanger Institute.

They found blood-derived iPSCs - which are increasingly common, due to the ease with which blood can be taken - also carried mutations but at a lower level than skin-derived iPS cells, and they had no UV damage.

Some 26.9 per cent of them, however, carried mutations in a gene called BCOR, which is an important gene in blood cancers.

Next the researchers investigated whether these BCOR mutations had any functional impact.

They differentiated the iPSCs, turning them into neurons and tracking their progress along the way.

[Read more: 4m funding for Cambridge scientists under Cancer Grand Challenges initiative]

Dr Rouhani said: What we saw was that there were problems in generating neurons from iPSCs that have BCOR mutations they had a tendency to favour other cell types instead. This is a significant finding, particularly if one is intending to use those lines for neurological research.

Analysis of the blood samples showed the BCOR mutations were not present within the patient.

So it seemed that the process of culturing cells increased the frequency of the mutations, which could have implications for other researchers working with cells in culture.

Typically, scientists using cell lines will screen them at the chromosomal level checking, for example, that the requisite 23 pairs of chromosomes are present.

Such analysis would not pick up the potentially major problems that this new study has identified, however,

The researchers warn that without looking in detail at the genomes of these stem cells, researchers and clinicians would be unaware of the underlying damage in them.

The DNA damage that we saw was at a nucleotide level, explained Prof Nik-Zainal. If you think of the human genome as like a book, most researchers would check the number of chapters and be satisfied that there were none missing. But what we saw was that even with the correct number of chapters in place, lots of the words were garbled.

Using whole genome sequencing, however, would enable errors to be discovered at the outset..

The cost of whole genome sequencing has dropped dramatically in recent years to around 500 per sample, though it's the analysis and interpretation that's the hardest bit, said Prof Nik-Zainal.

If a research question involves cell lines and cellular models, and particularly if we're going to introduce these lines back into patients, we may have to consider sequencing the genomes of these lines to understand what we are dealing with and get a sense of whether they are suitable for use.

Dr Rouhani adds: In recent years we have been finding out more and more about how even our healthy cells carry many mutations and therefore it is not a realistic aim to produce stem cell lines with zero mutations.

The goal should be to know as much as possible about the nature and extent of the DNA damage to make informed choices about the ultimate use of these stem cell lines.

If a line is to be used for cell based therapies in patients for example, then we need to understand more about the implications of these mutations so that both clinicians and patients are better informed of the risks involved in the treatment.

The research was funded by Cancer Research UK, the Medical Research Council and Wellcome, and supported by NIHR Cambridge Biomedical Research Centre and the UK Regenerative Medicine Platform.

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Many stem cell lines used for research and therapies carry large number of mutations, Cambridge researchers find - Cambridge Independent

VALENCIA, Calif. and MELBOURNE, Australia, Aug. 17, 2022 (GLOBE NEWSWIRE) -- AVITA Medical, Inc. (NASDAQ: RCEL, ASX: AVH), a regenerative medicine company that is developing and commercializing a technology platform that enables point-of-care autologous skin restoration for multiple unmet needs, announced today that a poster presentation on cell characterization and potential clinical benefits of the RECELL Autologous Cell Suspension System (RECELL System) for the treatment of stable vitiligo will be shared at the Controversies and Conversations in Laser & Cosmetic Surgery Annual Meeting. The conference will be held in Santa Barbara, CA, on August 19-21 bringing experts together to discuss controversial issues in cutaneous and aesethetic surgery or challenging therapeutic problems within dermatology.

Given the unique format of this meeting, we look forward to the presentation of RECELL and, more importantly, the conversation amongst dermatology experts as they discuss the unique attributes of this platform, including the potential for in-office point-of-care treatment in about 30 minutes, said Dr. Mike Perry, Chief Executive Officer of AVITA Medical. Following review by the FDA, we believe the RECELL System may well offer a welcome treatment option for patients seeking repigmentation for stable vitiligo lesions.

RECELL System Presentations

In the U.S., the RECELLSystem is indicated for the treatment of acute thermal burn wounds in patients 18 years of age and older or application in combination with meshed autografting for acute full-thickness thermal burn wounds in pediatric and adult patients. Physician-initiated research beyond the FDA approved indicationis not sponsored by AVITA Medicaland contains independentdata.

AVITA Medical is currently completing a pivotal trial for the use of the RECELL System for treatment of stable vitiligo. The vitiligo clinical trial aims to demonstrate safe and effective repigmentation when using the RECELL System in combination with phototherapy. AVITA anticipates FDA approval in 2023.

ABOUT AVITA MEDICAL, INC.

AVITA Medical, Inc. is a regenerative medicine company with a technology platform positioned to address unmet medical needs in burns, chronic wounds, and aesthetics indications. AVITA Medical Inc.s patented, and proprietary collection and application technology provides innovative treatment solutions derived from the regenerative properties of a patients own skin. The Companys lead product is the RECELL System, a device that enables healthcare professionals to Spray-On Skin Cells using a small sample of the patients own skin to create an autologous suspension. The RES Regenerative Epidermal Suspension is then sprayed onto the areas of the patient requiring treatment to regenerate natural healthy epidermis.

AVITA Medicals first U.S. product, the RECELL System, was approved by the U.S. Food and Drug Administration (FDA) in September 2018. The RECELL System is approved for acute partial-thickness thermal burn wounds in patients 18 years of age and older or application in combination with meshed autografting for acute full-thickness thermal burn wounds in pediatric and adult patients. In February 2022, the FDA reviewed and approved the PMA supplement for RECELL Autologous Cell Harvesting Device, an enhanced RECELL System aimed at providing clinicians a more efficient user experience and simplified workflow.

The RECELL System is used to prepare Spray-On Skin Cells using a small amount of a patients own skin, providing a new way to treat severe burns, while significantly reducing the amount of donor skin required. The RECELL System is designed to be used at the point of care alone or in combination with autografts depending on the depth of the burn injury. Compelling data from randomized, controlled clinical trials conducted at major U.S. burn centers and real-world use in more than 15,000 patients globally, reinforce that the RECELL System is a significant advancement over the current standard of care for burn patients and offers benefits in clinical outcomes and cost savings. Healthcare professionals should read the INSTRUCTIONS FOR USE - RECELL Autologous Cell Harvesting Device ( https://recellsystem.com/ ) for a full description of indications for use and important safety information including contraindications, warnings, and precautions.

In international markets, our products are approved under the RECELL System brand to promote skin healing in a wide range of applications including burns, chronic wounds, and aesthetics. The RECELL System is TGA-registered in Australia, received CE-mark approval in Europe, and received Japans Pharmaceuticals and Medical Devices Act (PMDA) approval for burns in Japan.

CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS

This press release includes forward-looking statements. These forward-looking statements generally can be identified by the use of words such as anticipate, expect, intend, could, may, will, believe, estimate, look forward, forecast, goal, target, project, continue, outlook, guidance, future, other words of similar meaning and the use of future dates. Forward-looking statements in this press release include, but are not limited to, statements concerning, among other things, our ongoing clinical trials and product development activities, regulatory approval of our products, the potential for future growth in our business, and our ability to achieve our key strategic, operational, and financial goal. Forward-looking statements by their nature address matters that are, to different degrees, uncertain. Each forward-looking statement contained in this press release is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statement. Applicable risks and uncertainties include, among others, the timing and realization of regulatory approvals of our products; physician acceptance, endorsement, and use of our products; failure to achieve the anticipated benefits from approval of our products; the effect of regulatory actions; product liability claims; risks associated with international operations and expansion; and other business effects, including the effects of industry, economic or political conditions outside of the companys control. Investors should not place considerable reliance on the forward-looking statements contained in this press release. Investors are encouraged to read our publicly available filings for a discussion of these and other risks and uncertainties. The forward-looking statements in this press release speak only as of the date of this release, and we undertake no obligation to update or revise any of these statements.

This press release was authorized by the review committee of AVITA Medical, Inc.

FOR FURTHER INFORMATION:

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RECELL System Data to be Presented at the Controversies and Conversations in Laser & ... - The Bakersfield Californian

PRINCETON, N.J., Aug. 16, 2022 (GLOBE NEWSWIRE) -- Integra LifeSciences Holdings Corporation (NASDAQ:IART), a leading global medical technology company, today announced that Dr. Richard Caruso, founder and former chairman and CEO of Integra LifeSciences passed away over the past weekend.

Dr. Richard Caruso made an impact on not only the medical technology industry, but more importantly, on the countless lives around the world who have benefited from the products and technologies that Integra LifeSciences has today, said Stuart Essig, chairman of the board at Integra LifeSciences. His vision, transformative ideas and entrepreneurial spirit have revolutionized the way surgeons treat their patients in the field of regenerative medicine.

Dr. Caruso founded Integra LifeSciences in 1989 with a vision that the human body could be enabled to regenerate many of its own damaged or diseased tissues, paving the way for a new discipline back then known as regenerative medicine. Through his vision, Integra became the first company to develop and bring to market a tissue regeneration product, Integra Dermal Regeneration Template, which was approved by the FDA in 1996 as a skin replacement system with a claim for regeneration of dermal tissue for the treatment of life-threatening burns and repair of scar contractures. That technology led to the development of DuraGen Dural Graft Matrix, for repair of the dura mater, the protective covering of the brain after cranial and spine surgery, and NeuraGen Nerve Guide, which creates a conduit for axonal growth across a severed nerve.

Dr. Caruso served as Integra's chairman from 1992 until 2011, and served as CEO from 1992 to 1997. In addition, he served on the Board of Susquehanna University and the Baum School of Art. Dr. Caruso received his B.S. degree from Susquehanna University, an M.S.B.A. degree from Bucknell University, and a Ph.D. degree from the London School of Economics, University of London. He was also the founder and director of The Uncommon Individual Foundation, a non-profit foundation that encourages individuals to form and follow their dreams of personal success and become the entrepreneurs of their personal lives.

About Integra LifeSciencesIntegra LifeSciences is a global leader in regenerative tissue technologies and neurosurgical solutions dedicated to limiting uncertainty for clinicians so they can focus on providing the best patient care. Integra offers a comprehensive portfolio of high quality, leadership brands that include AmnioExcel, Aurora, Bactiseal,BioD, CerebroFlo, CereLinkCertasPlus, Codman, CUSA, Cytal, DuraGen, DuraSeal, Gentrix, ICP Express, Integra, Licox, MAYFIELD, MediHoney, MicroFrance, MicroMatrix, NeuraGen, NeuraWrap, PriMatrix, SurgiMend, TCC-EZand VersaTru. For the latest news and information about Integra and its products, please visitwww.integralife.com.

Investor Relations Contact:Chris Ward(609) 772-7736chris.ward@integralife.com

Media Contact:Laurene Isip(609) 208-8121laurene.isip@integralife.com

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/fe4238dd-d2f8-487f-8f14-19e855e9b041.

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Integra LifeSciences Announces the Passing of Dr. Richard Caruso, Founder and Former Chairman and CEO - GlobeNewswire

Under-resourced high school students need to be familiarized with multiple components of research in order to give back to their communities, said Dolores Caffey Fleming, MS, MPH.

Fleming is the director of Project STRIDE (Students Training in Research Involving Disparity Elimination), Project STRIDE II, and Project ExSTRM (Exposing Students To Regenerative Medicine).

The STRIDE programs are funded by the Doris Duke Charitable Foundation while the ExSTRM program is funded by the California Institute of Regenerative Medicine (CIRM). According to Fleming, the goal of all the programs is to allow students to be exposed to research and various healthcare careers in order for them to give back to their communities.

This year, these programs were sort of combined as a lot of the activities that they did were interconnected. These research programs for high schoolers at Charles R. Drew University (CDU) have been consistently supported by Jay Vadgama, Ph.D., the Vice President for Research and Health Affairs (CDU), and have continued to operate for the past several years

Before actually going onto campus, we had to do CITI (Collaborative Institutional Training Initiative) training before we entered any labs or facilities. We took seven courses ranging from Biosafety for Researchers to Good Clinical Practice. After finishing, I had a virtual introduction with my mentor, Dr. Juanita Booker-Vaughns, and we talked about potential project ideas and her experience in research.

For the first week, Elizabeth Delgado, a project coordinator, taught us and administered quizzes from the university about lab safety, chemical hazards, and the Code of Conduct. The next week, I personally got to shadow some professionals in the Cancer Division lab and was able to watch them perform procedures like the Western Blot Test and Polymerase Chain Reactions (PCR). Although this was not related to my project, it was cool to learn and observe an important procedure. Many Tuesdays and Thursdays were also reserved for leadership training and resume-building classes.

A Polymerase Chain Reaction, or PCR. (Photo by Shaun Thomas)

My research project was centered around examining colorectal cancer (CRC) risk factors in a specific area of Los Angeles County known as Service Planning Area (SPA) 6. With my mentors help, we looked at public health data about all these risk factors in SPA 6, as opposed to L.A. County as a whole.

I first conducted literature about colorectal cancer risk factors in general ranging from biological factors like Inflammatory Bowel Disease (IBD) to behavioral health factors like diet. After that, using the data from the Key Indicators of Health Report (2017) by Los Angeles Countys Department of Public Health, I created graphs and analyzed the data. To put everything together, I created a poster showcasing my findings.

I had the chance to interview one student from each of the three cohorts.

I first interviewed Ivan Ixtlilco, a Project STRIDE senior at King Drew Magnet High School, whose project was about how urban ecology affects epigenetics and how this, in turn, increases the risk of cardiovascular disease, he said. He added on about how his mentor introduced him to a whole variety of careers in research that he had no idea about.

Afia Ahmed, a Project STRIDE II rising second-year student at UC Irvine said, Project STRIDE allowed [her] to gain a foundation for building a whole manuscript, skimming through articles for crucial information. She said these skills were beneficial for her public health classes at UCI.

She also pointed out some key differences between the two. Now that she is doing STRIDE II, she mentioned doing a manuscript and going more into depth with her research on the mental health of Asian American females who are infertile in order to build an abstract and submit her abstract to conferences. She noted that there was a significant literature gap between Asian American female infertility and female infertility in general.

Ricardo Rodriguez, an ExSTRM senior at St. John Bosco High School, focused on a project that involved more lab work: ancestry-specific expression of stem-like markers in breast cancer cells. He believes stem cells are the future of research and can even be key to processes like regeneration. However, he also believes that governments will decide the fate of using this research. He had the opportunity to present his poster at the CIRM SPARK conference which took place on August 3 in Oakland, Calif.

Shaun Thomas with Dr. Jay Vadgama at the symposium. (Photo courtesy of Shaun Thomas)

The climax of the program was the Charles Drew Symposium which took place on August 5. At the symposium, some of us were chosen to present our projects in front of guests, university faculty, and all of our mentors. After the presentations, we all presented our posters in a gallery. The two-hour event showcased the culmination of our work over.

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Column: My summer research experience at Charles R. Drew University for Medicine and Science - Los Angeles Times

NEW YORK Tessa Therapeutics said on Wednesday that it has dosed the first lymphoma patient in a Phase Ib trial of its investigational CAR T-cell therapy TT11 plus Bristol Myers Squibb's Opdivo (nivolumab).

The trial, dubbed ACTION, is designed to evaluate the autologous CD30-directed CAR T-cell therapy plus the PD-1 inhibitor as second-line treatment for up to 14 patients with CD30-positive relapsed or refractory classical Hodgkin lymphoma after chemotherapy.

Singapore-based Tessa Therapeutics is calling the treatment regimen evaluated in the trial a "sandwich" design. Patients enrolled in the trial will receive two cycles of Opdivo followed by a lymphodepleting chemotherapy regimen, then a single infusion of the autologous TT11 CAR T-cell therapy, then another two cycles of Opdivo. The primary goal of the trial is to evaluate the treatment's safety and tolerability, and secondary aims include overall response rate, duration of response, and progression-free survival.

Tessa is also evaluating TT11 as a monotherapy for CD30-positive relapsed or refractory classical Hodgkin lymphoma in the Phase II CHARIOT trial. Initial data from that study showed that the cell therapy had a favorable safety profile and promising efficacy, with a 57.1 percent complete response rate and a 71.4 percent overall response rate among 14 patients. Tessa expects to begin the pivotal Phase II portion of that trial later this year.

"We welcome the opportunity to capitalize on this clinical progress by investigating TT11 as a second-line combination therapy, which offers the opportunity to greatly increase the patient population who could potentially benefit from this course of care," John Ng, chief technology officer and acting CEO of Tessa, said in a statement.

The firm believes that combining the CAR T-cell therapy with Opdivo will improve its efficacy and offer classical Hodgkin lymphoma patients a second-line treatment option that is more tolerable than chemotherapy. The US Food and Drug Administration has designated TT11 a regenerative medicine advanced therapy and the European Medicines Agency has designated it a priority medicine.

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Tessa Therapeutics Starts Trial of CAR T-Cell Therapy, BMS's Opdivo in Classical Hodgkin Lymphoma - Precision Oncology News

This includes the analogous nature of articular cartilage, muscle fascia, and intervertebral disc confirmed by way of comparative Scanning Electron Microscope analysis

PENSACOLA, Fla., Aug. 15, 2022 /PRNewswire/ -- Regenative Labs, a leading HCT/P manufacturer, has co-authored a pioneering papertogether with experts from The Institute of Regenative Medicine and the Department of Pharmacology and Chemical Biology, Baylor College of Medicine.

"This paper is a market disruptorand will be our most significant paper released to date. This is the first literature thatwe are aware of to utilize Scanning Electron Microscope (SEM) images of actual tissue samples to objectively demonstrate on a qualitative and quantitative basis that collagen structural tissuematrices in our post-processed Wharton's Jelly allografts and those in articular cartilage, muscle fascia, and intervertebral discs are analogous," said Regenative Labs CEO, Tyler Barrett.

This research highlights our commitment to the Regenerative Medicine community. We believe the combination of our IRB-approved observational studies, peer-reviewed publications, ISO-certified laboratory processes, and our commitment to compliance with FDA and American Association of Tissue Banks (AATB) standards, sets the standard for HCT/P manufacturers. Regenative Labs has pioneered the use of perinatal tissue allografts and is pleased that this paper supports our current homologous use practices, consistent with our 361 status.

Currently, the treatments for the Intervertebral Disc (DDD) range in cost and effectiveness from an $8 bottle of Ibuprofen to $150,000 for spinal fusion (1). Neither of these treatment options target the foundational issue of ECM cartilage breakdown in the intervertebral discs. By age 35, 30% of people show signs of DDD; by age 60, this increases to 90% (2). That we are aware of, this is the first perinatal tissue allograft in the medical marketplace that may be applied in a homologous fashion per FDA 361 guidelines to replace or supplement missing or damaged connective tissue. All other non-surgical paradigms focus on symptom management and do not address the disc's collagen structural degeneration. In collaboration with medical providers across the country, we are actively investigating additional homologous use applications for this technology in tissue defects associated with the load-bearing joints of the knee, hip, shoulder, spine, ankle, and foot.

Billions of dollars are spent annually on the surgical care and treatment of patients suffering from degeneration of load-bearing joints and intravertebral discs. We are honored to offer patients evidence-based and structural tissue defect-specific non-surgical applications on a global scale.

Additional Sources:

About Regenative Labs: Regenative Labs produces regenerative medicine products to address the root cause of a patient's conditions using Wharton's Jelly innovations rather than masking the pain with other treatments. Regenative Labs works closely with scientists, physicians, hospitals, and surgery centers to constantly monitor and improve patient progress and outcomes for new product development. Formed by veteran industry professionals familiar with daily challenges of innovations in healthcare, the company providesnon-addictive, non-invasive options for patients. Regenative Labs's expert product research and development team compliesFDA guidelines of minimal manipulation for homologous use. The company adheres to AATB and FDA guidelines. Learn more at Regenative's website: http://www.regenativelabs.com

SOURCE Regenative Labs

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Regenative Labs announces groundbreaking Wharton's Jelly research demonstrating HCT/P compliance after processing - PR Newswire

Each year, Baylor College of Medicine faculty are recognized for their outstanding published scientific contributions to clinical and basic science research over the past three years through the Michael E. DeBakey M.D. Award for Excellence in Research.

This years 2022 recipients are Dr. Peter Hotez and Dr. Maria Elena Bottazzi (joint awardees), Dr. Joseph Hyser, Dr. Katherine King, Dr. Irina Larina, Dr. Scott A. LeMaire and Dr. Ying Shen (joint awardees) and Dr. Sundeep Keswani.

Each year we celebrate and honor researchers from our Baylor community who have made significant contributions to improving healthcare, said Dr. Paul Klotman, Baylor president, CEO and executive dean. These awards celebrate the legacy of innovation in research and medicine set forth by Dr. DeBakey.

The awards, named in honor of pioneering heart surgeon Dr. Michael E. DeBakey, the first president of Baylor College of Medicine, and sponsored by the DeBakey Medical Foundation, include a commemorative medallion and funds to support further research.

The eight researchers were recognized and presented their work at a small in-person ceremony on Wednesday, Aug. 17.

It is an honor to recognize this group. They represent the continued work here at Baylor to improve health and humanity and each researcher demonstrates the impact to science and the community, said Dr. Mary Dickinson, senior vice president and dean of research at Baylor.

Dr. Maria Elena BottazziAssociate dean of the National School for Tropical Medicine at Baylor College of Medicine and co-director of the Texas Children's Hospital Center for Vaccine Development

Dr. Bottazzi is an internationally recognized tropical and emerging disease vaccinologist, global health advocate and co-creator of a patent-free, open science COVID-19 vaccine technology that led to the development of Corbevax, a COVID-19 vaccine for the world. She pioneers and leads the advancement of a robust infectious and tropical disease vaccine portfolio tackling diseases such as coronavirus, hookworm, schistosomiasis and Chagas that disproportionally affect the worlds poorest populations. She also has established innovative partnerships in Latin America, the Middle East and Southeast Asia, making significant contributions to innovative educational and research programs, catalyzing policies and disseminating science information to reach a diverse set of audiences.

As global thought-leader she has received national and international highly regarded awards, has more than 280 scientific papers and participated in more than 250 conferences worldwide. She is a member of the National Academy of Science of Honduras and an Emerging Leader in Health and Medicine of the National Academy of Medicine in the U.S.

Bottazzi is a fellow of the American Society of Tropical Medicine and Hygiene (ASTMH), the Executive Leadership in Academic Medicine (ELAM) and the Leshner Leadership Institute for Public Engagement and senior fellow of the American Leadership Forum (ALF). Forbes LATAM in 2020 and 2021 selected Bottazzi as one of 100 Most Powerful Women in Central America. Bottazzi has served in several national academies ad-hoc committees and serves as co-chair of the Vaccines and Therapeutics Taskforce of the Lancet Commission on COVID-19. In 2022, alongside Dr. Peter Hotez, she was nominated by Congresswoman Lizzie Fletcher of Texas for the Nobel Peace Prize.

Dr. Peter HotezDean of the National School of Tropical Medicine at Baylor College of Medicine and co-director of the Texas Childrens Hospital Center for Vaccine Development

Dr. Hotez is an internationally recognized physician-scientist in neglected tropical diseases and vaccine development. As co-director of the Texas Childrens Center for Vaccine Development, he leads a team and product development partnership for developing new vaccines for hookworm infection, schistosomiasis, leishmaniasis, Chagas disease and SARS/MERS/SARS-2 coronavirus, diseases affecting hundreds of millions of children and adults worldwide, while championing access to vaccines globally and in the U.S.

In December 2021, Hotez led efforts at the Texas Childrens Center for Vaccine Development to develop a low-cost recombinant protein COVID vaccine for global health, resulting in emergency use authorization in India. In 2022 Hotez and his colleague Dr. Maria Elena Bottazzi were nominated for the Nobel Peace Prize for their work to develop and distribute a low-cost COVID-19 vaccine to people of the world without patent limitation.

In 2014-16, he served in the Obama Administration as U.S. Envoy, focusing on vaccine diplomacy initiatives between the U.S. government and countries in the Middle East and North Africa. In 2018, he was appointed by the U.S. State Department to serve on the Board of Governors for the U.S.-Israel Binational Science Foundation, and he is frequently called on frequently to testify before U.S. Congress. He has served on infectious disease task forces for two consecutive Texas governors. For these efforts in 2017 he was named by FORTUNE Magazine as one of the 34 most influential people in healthcare, while in 2018 he received the Sustained Leadership Award from Research!America.

Most recently as both a vaccine scientist and autism parent, he has led national efforts to defend vaccines and to serve as an ardent champion of vaccines going up against a growing national antivax threat. In 2019, he received the Award for Leadership in Advocacy for Vaccines from the American Society of Tropical Medicine and Hygiene. In 2021 he was recognized by scientific leadership awards from the Association of American Medical Colleges and the American Medical Association, in addition to being recognized by the Anti-Defamation League with its annual Popkin Award for combating antisemitism.

Dr. Joseph HyserAssistant professor of molecular virology and microbiology and member of the Alkek Center for Metagenomics and Microbiome Research

Dr. Joseph Hysers research work is dedicated to improving our understanding of host-pathogen interactions. He has focused on characterizing host signaling pathways that enteric viruses, such as rotavirus, destabilize to cause gastrointestinal disease. His work stands out because it is shifting prevailing paradigms within the field.

In recent work, Hyser used calcium biosensor cell lines and organoids he developed to perform long-term live calcium imaging throughout rotavirus infections. This work is paradigm shifting because it firmly established that rotavirus increase calcium through hundreds of discrete calcium signaling events rather than a general, monophasic increase in cytosolic calcium levels. This study also led to the discovery of multiple distinct types of calcium signals present at different stages of the infection.Another study showed that calcium-conducting viroporins are a broadly conserved strategy used by viruses to exploit host calcium signaling pathways. This finding has opened the door to identify commonly exploited host pathways for which host-targeted antiviral drugs could be developed.

Recently, Hyser published the first direct evidence that viruses can trigger aberrant calcium signaling in uninfected cells by exploiting a host paracrine signaling pathway. Live imaging data show calcium signals coming from rotavirus-infected cells and spreading to surrounding uninfected cellsa type of signal called intercellular calcium waves. He found that eliminating the calcium waves severely reduced rotavirus replication, suggesting that rotavirus has evolved to co-opt this host intercellular signal to increase its replication. Taken together, Hysers work establishes a new mechanism by which viruses commandeer nearby uninfected cells to contribute to pathogenesis through paracrine signaling.

Dr. Katherine KingAssociate professor of pediatrics infectious diseases and member of the Dan L Duncan Comprehensive Cancer Center and Center for Cell and Gene Therapy

Dr. Kings research focuses on the effects of infection and inflammation on primitive hematopoiesis. As a pediatric infectious diseases physician at Texas Childrens Hospital, King recognized the need to understand bone marrow suppressive effects of chronic infection, and she led the field to characterize hematopoietic stem cell responses in the context of animal models of infection. Her review on the topic of inflammatory modulation of hematopoietic stem cells altered the way the field views the interactions between systemic inflammation and stem cells, with continuing repercussions in the fields of malignant and nonmalignant hematology, aging and immunology.

Using a multidisciplinary approach, she has pioneered the concept that hematopoietic stem cells are extremely sensitive to inflammatory signals in the bone marrow environment. Her research has defined a role for inflammatory signaling in bone marrow suppression following chronic infection and in the emergence of clonal hematopoiesis, a recently defined phenomenon that drives cancer risk and cardiovascular disease in advanced age.

Over the past three years, her research efforts have resulted in 9 senior-author research articles in leading journals in her field including Cell Stem Cell, Cell Reports, and eLife. Kings highly innovative and impactful work at the intersection of immunology and hematology has made her an international leader in the field of stem cell biology. She is a skilled clinician, a healthcare advocate, scientist, administrative leader and trusted mentor.

Dr. Irina LarinaAssociate professor of integrative physiology

Dr. Irina Larinas lab is dedicated to the development of new biophotonic technologies to define pathways involved in live embryo progression and, specifically, cardiac development. She also applies her new biophotonic methods to image developmental processes in various mouse models to elucidate pathophysiological mechanisms underlying reproductive disorders. Larina also develops data processing methods that enable her to uncover new information about congenital defects and reproductive disorders that reveal the dynamics of developmental processes, which have not been accessible before.

Most recently she used second harmonic generation microscopy to image collage fibers in embryonic hearts, revealing a link between structural collagen and regional contractility that suggested a regulatory role for cardiomyocyte contractility in establishing mechanical homeostasis in the developing heart. These findings revealed new features of the biochemical alterations found in congenital heart defects and heart failure. In addition, her lab recently established a method to study the interactions between genetic and mechanical factors in both normal and pathogenic cardiogenesis in vivo, such as arrhythmias.

In the area of reproduction, Larinas innovative biophotonics technology provided direct visualization of the movement of oocytes and embryos in the fallopian tube. Identifying abnormalities in this process is critical for defining defects in mammalian fertilization and embryogenesis. Using her new approach, which combines optical coherence tomography with intravital imaging, Larina showed that cilia do not drive directional oocyte/embryo transport. The timing of the oocyte/embryo transport is primarily regulated by smooth muscle dynamics at different locations within the oviduct.

Dr. Scott A. LeMaireJimmy and Roberta Howell Professor of Cardiovascular Surgery, vice chair for research in the Michael E. DeBakey Department of Surgery, director of research in the Division of Cardiothoracic Surgery and professor of molecular physiology and biophysics

Dr. LeMaires primary clinical interest focuses on the management of patients with thoracic aortic disease, with a particular emphasis on treatment of aortic dissection and thoracoabdominal aortic aneurysms. His corresponding research program focuses on organ protection during aortic surgery, genetic aspects of thoracic aortic disease and molecular mechanisms of aortic degeneration.

He has received funding from the National Institutes of Health, the American Heart Association, the Thoracic Surgery Foundation and the Marfan Foundation for his research studying the pathobiology of thoracic aortic aneurysms and aortic dissection. LeMaire is a past-president of the Association for Academic Surgery and is the current editor-in-chief of the Journal of Surgical Research.

LeMaire also serves as a physician associate in the Department of Cardiovascular Surgery at the Texas Heart Institute and Baylor St. Lukes Medical Center.

Dr. Ying ShenProfessor of surgery and director of the Aortic Disease Research Laboratory

Dr. Shens research focuses on understanding the development of vascular diseases. She became the director of the Aortic Disease Research Laboratory in 2008, and has since focused on aortic aneurysms and dissections, highly lethal but poorly understood diseases. She has worked closely with collaborator Dr. Scott LeMaire and together, they have built a translational research program and developed several research directions to investigate the mechanisms of aortic injury, repair and remodeling. The ultimate goal of her research is to develop pharmacological treatments to prevent progressive aortic destruction, maladaptive remodeling and disease deterioration.

Dr. Sundeep KeswaniProfessor of surgery, pediatrics and obstetrics and gynecology, division chief of pediatric surgery and surgical director of basic science research at Texas Childrens Hospital

Dr. Sundeep Keswanis lab, the Laboratory for Regenerative Tissue Repair, is focused on understanding the molecular mechanism that underlies the fetus ability to regeneratively heal cutaneous wounds, as well as the development of novel therapies to achieve scarless wound healing in postnatal tissues, specifically the interaction of inflammation and extracellular matrix to drive fibrotic responses within human skin in response to injury. Most recently he has shown that bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection and that Interleukin-10 producing T lymphocytes (TR1 cells) reduce dermal scarring. In addition to his work in skin, his group also has discovered that hyaluronan attenuates tubulointerstitial scarring in kidney injury.During the last three years, he has published his research outcomes in highly prestigious journals such as Science, Annals of Surgery and JCI Insight.

Keswani also serves as a governor of the American College of Surgeons and continually publishes articles that examine the state of research and surgery, keeping surgeon-scientists highly relevant nationally.

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Baylor College of Medicine recognizes research excellence with DeBakey Awards - Baylor College of Medicine News

GRAND RAPIDS, Mich. (WOOD) The soldiers of our immune system were long thought to be fueled only by the foods we eat. However, researchers at Van Andel Institute believe the findings from their new study reveal T cells have a much wider appetite than originally thought.

Every process in the body is powered by metabolism, which in turn is fueled by the nutrients we consume through our diet, Russell Jones, Ph.D., chair of Van Andel Institutes Department of Metabolism and Nutritional Programming said. We found that immune cells are much more flexible in selecting the nutrient fuels they consume and, importantly, that they prefer some nutrients that were previously dismissed as waste. This understanding is crucial for optimizing T cell responses and developing new strategies for boosting our ability to fight off disease.

Jones, who is the co-author of the study published this week in Cell Metabolism, says the findings could create a path for personalized dietary recommendations that would supercharge immune cells and provide more effective therapies for cancer and other diseases.

Joneses research took a new approach to studyin T cells. In previous studies, the cells were grown in lab dishes with nutrient-contatining media. But Jones believed those nutrients were similar to a diet of eggs and toast. This time, Jones and his colleagues developed a more diverse sample of nutrients for the research and the outcome was much different.

We found that, when we offer them a full buffet, these cells actually prefer a wider array of fuels than previously believed, Jones said. This has major implications for how we tailor dietary recommendations as ways to promote health and combat disease.

Jones explains the research through what they discovered from lactate, a cellular waste that causes muscle aches and pains and a byproduct of cancer cells that allows the disease to attack other tissue and avoid the immune system. When the T cells were given the choice between glucose and lactate, they chose the lactate to power their energy production which enhanced their overall function.

According to VAI, there is research that suggests too much lactate is bad for T cells, but Jones work provides the idea that small amounts may increase their overall function.

Jones and his team plan to take their findings and use them to take a closer look at the unique connection between metabolism and the immune system to learn more about how they work together.

Hear from Dr. Jones below.

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New study could change what we eat to supercharge immune system and fight disease - WOODTV.com

Ecological model

We start with an ecological model of resident host-pathogen dynamics that assumes these populations are, respectively, genetically homogeneous. The ecological model underlies the evolutionary model we develop later. A complete description of the model, and the methods of analysis that follow, can be found in theSupplementary Information.

We consider a population of hosts classified according to their sex and disease status. At time t, there are Si=Si(t) sex-i individuals not infected by the pathogen, but susceptible to future infection (i=f for females, i=m for males). At time t there are also Ii=Ii(t) sex-i individuals who are not only infected with the pathogen but also able to transmit their infection to others. Our specific goal in this section is to develop a mathematical description of how the numbers of hosts in the various classes change over time.

The number of hosts in the population changes as a result of birth events. Following previous work44,45, we model the host mating rate using the harmonic mean of the population sizes of females and males. Assuming a one-to-one birth sex ratio, then newly born hosts of either sex join the population at rate (frac{b({S}_{f}+{I}_{f})({S}_{m}+{I}_{m})}{N}) where b>0, and N=N(t) denotes the total population size at time t. We assume that newborns produced by susceptible mothers are, themselves, susceptible. By contrast, we suppose that newborns produced by infected mothers acquire their mothers infection with probability v, where v is what we have called the vertical transmission rate31. Host number also changes because of death events. Hosts in every class experience natural mortality at per-capita rate N, where is a positive constant. Hosts infected by the pathogen also experience disease-related mortality at per-capita rate i (a measure of pathogen virulence) (Fig.7).

This model incorporates two sexes (females in red and males in blue) and vertical transmission (dashed line). The flow between compartments is represented by arrows and expressions next to each arrow represent the flow rate. Evolving phenotypes and drivers of their evolution are indicated in green and purple, respectively. Source data are provided as a Source Data file.

Numbers of hosts in any particular class changes as their disease-status changes. For example, we allow infected individuals to recover at per-capita rate i (a measure of host immunocompetence). We assume that, upon recovery, hosts move immediately into the appropriate susceptible group. In this way, we ignore the possibility that recovery implies immunity to subsequent infection. The disease status of hosts can also change because of horizontal disease-transmission events. We approach horizontal transmission in a standard way and assume that susceptible sex-i hosts acquire the pathogen horizontally from their infected sex-j counterparts at a total rate of SiijIj. Here, ij is a constant that reflects the transmissibility of the pathogen. We assume that when a host acquires an infection horizontally, it immediately becomes infectious (Fig.7).

The model described above is summarised mathematically using the following system of differential equations:

$$frac{d{S}_{f}}{dt}=frac{b({S}_{f}+(1-v){I}_{f})({S}_{m}+{I}_{m})}{N}+{gamma }_{f}{I}_{f}-{S}_{f}{beta }_{ff}{I}_{f}-{S}_{f}{beta }_{fm}{I}_{m}-mu N{S}_{f}$$

(1a)

$$frac{d{S}_{m}}{dt}=frac{b({S}_{f}+(1-v){I}_{f})({S}_{m}+{I}_{m})}{N}+{gamma }_{m}{I}_{m}-{S}_{m}{beta }_{mf}{I}_{f}-{S}_{m}{beta }_{mm}{I}_{m}-mu N{S}_{m}$$

(1b)

$$frac{d{I}_{f}}{dt}=frac{bv{I}_{f}({S}_{m}+{I}_{m})}{N}+{S}_{f}{beta }_{ff}{I}_{f}+{S}_{f}{beta }_{fm}{I}_{m}-({gamma }_{f}+{alpha }_{f}+mu N){I}_{f}$$

(1c)

$$frac{d{I}_{m}}{dt}=frac{bv{I}_{f}({S}_{m}+{I}_{m})}{N}+{S}_{m}{beta }_{mf}{I}_{f}+{S}_{m}{beta }_{mm}{I}_{m}-({gamma }_{m}+{alpha }_{m}+mu N){I}_{m}.$$

(1d)

Under a reasonable set of conditions, the previous system tends, over time, to an equilibrium state in which infections are endemic.

To study how pathogens disease-induced mortality and the hosts immune system respond to selection, we assume that each faces a life-history trade-off.

First, the pathogens ability to transmit horizontally trades off against the duration of any given infection it establishes. Following the previous authors30,46,47, we capture this trade-off by assuming

$${beta }_{ij}=beta ({alpha }_{j})=frac{{beta }_{max }{alpha }_{j}}{{alpha }_{j}+d}quad ,{{mbox{for}}},,j=f,;m,$$

(2)

where ({beta }_{max },,d , > , 0) are constants. Equation (2) implies that the nature of the trade-off faced by a pathogen is the same in both female and male hosts. Specifically, a pathogen can only increase its rate of horizontal transmission by increasing the disease-induced mortality rate experienced by its host (which, in turn, reduces the duration of infection). Equation (2) also says the horizontal transmission rate saturates at ({beta }_{max }) (independent of host sex), and does so more quickly as the parameter d is reduced (again, independent of host sex). Note also that Equation (2) does not depend on i: the sex of the susceptible host to whom the pathogen is transmitted.

For their part, hosts face a trade-off between investing resources in their immune system and their reproductive success. Increased immune investment is reflected in an increased recovery rate. To capture the hosts trade-off, then, we treat birth rate b as a decreasing function of the recovery rate. Moreover, we assume that the decrease in b is experienced by the host regardless of its disease status. In other words, we assume that cost associated with the immune system is an ongoing one, incurred mainly because of maintenance27 (this assumption model innate immunocompetence best) rather than being due to the activation that follows an infection48 (this assumption would model adaptive immunocompetence best). As noted in the Discussion, we relax this assumption in theSupplemental Material and compare the results for maintenance and activation costs. As an example, here, we point to evidence that shows female sex hormones enhance the immune system but simultaneously reduce the likelihood of conception and increase the chances of spontaneous abortion49,50,51. In mathematical terms, we capture the hosts trade-off using

$$b=b({gamma }_{f},{gamma }_{m})={b}_{max },{e}^{-{c}_{f}{gamma }_{f}^{2}},{e}^{-{c}_{m}{gamma }_{m}^{2}}$$

(3)

where ci reflects the rate at which fertility is reduced as sex-i immune function is increased (cost of recovery above). Equation (3) generalises the birth rate functions used previously27,48 to our sex-specific setting. The fact that b in this equation depends on both f and m reflects the fact that the reduced fertility of one mate affects the fertility of its partner16.

Our approach to modelling the co-evolution of host and pathogen is rooted in the adaptive-dynamics methodology52,53,54. For the pathogen population, we build a fitness expression that measures the success of a rare mutant strain in a population close to the endemic equilibrium established by the system (1) (indicated as ({bar{S}}_{i}), ({bar{I}}_{i}), and (bar{N})). Assuming that the mutant strain of pathogen is associated with a disease-induced mortality rate equal to ({tilde{alpha }}_{i}) in sex-i hosts, the number of mutant infections, ({tilde{I}}_{i}={tilde{I}}_{i}(t)) changes according to

$$frac{d{tilde{I}}_{f}}{dt}=frac{bv{tilde{I}}_{f}({bar{S}}_{m}+{bar{I}}_{m})}{bar{N}}+{bar{S}}_{f}beta ({tilde{alpha }}_{f}){tilde{I}}_{f}+{bar{S}}_{f}beta ({tilde{alpha }}_{m}){tilde{I}}_{m}-({gamma }_{f}+{tilde{alpha }}_{f}+mu bar{N}){tilde{I}}_{f}$$

(4a)

$$frac{d{tilde{I}}_{m}}{dt}=frac{bv{tilde{I}}_{f}({bar{S}}_{m}+{bar{I}}_{m})}{bar{N}}+{bar{S}}_{m}beta ({tilde{alpha }}_{f}){tilde{I}}_{f}+{bar{S}}_{m}beta ({tilde{alpha }}_{m}){tilde{I}}_{m}-({gamma }_{m}+{tilde{alpha }}_{m}+mu bar{N}){tilde{I}}_{m}.$$

(4b)

The system in (4) is linear and its long-term behaviour is determined by a dominant Lyapunov exponent of the mapping. We capture the information provided by the dominant Lyapunov exponent with the pathogen-fitness function, ({W}_{alpha }({tilde{alpha }}_{f},{tilde{alpha }}_{m},{alpha }_{f},{alpha }_{m})) using techniques laid out by the ref. 55 (see alsoSupplemental Information). When this function is greater than 1 the mutant invades and eventually displaces56 the resident strain associated with the i phenotype. When the function ({W}_{alpha }({tilde{alpha }}_{f},{tilde{alpha }}_{m},{alpha }_{f},{alpha }_{m})) is less than 1 the mutant does not invade and is eliminated from the population. With these facts in mind, we say that selection acts to move i in the direction given by the sign of (frac{partial {W}_{alpha }}{partial {tilde{alpha }}_{i}}{left|right.}_{tilde{alpha }=alpha }) where (tilde{alpha }=alpha) is shorthand for ({tilde{alpha }}_{i}={alpha }_{i}) for all i. Specifically, when this partial derivative is positive i is increasing, and when it is negative i is decreasing.

We follow a similar procedure for the host population by introducing, into the equilibrium population, a rare mutant-type host genotype that results in a recovery rate of ({hat{gamma }}_{i}) when expressed by sex-i hosts. We denote the numbers of susceptible and infected sex-i mutant-type hosts as ({hat{S}}_{i}) and ({hat{I}}_{i}), respectively. We assume that hosts are diploid, and so, strictly speaking, the hosts who contribute to ({hat{S}}_{i}) and ({hat{I}}_{i}) categories are heterozygotes (the numbers of homozygote mutants are negligible). While it remains rare, the dynamics of the mutant-host lineage can be described using

$$frac{d{hat{S}}_{f}}{dt}= frac{frac{b({hat{gamma }}_{f},{gamma }_{m})}{2}({hat{S}}_{f}+(1-v){hat{I}}_{f})({bar{S}}_{m}+{bar{I}}_{m})+frac{b({gamma }_{f},{hat{gamma }}_{m})}{2}({bar{S}}_{f}+(1-v){bar{I}}_{f})({hat{S}}_{m}+{hat{I}}_{m})}{bar{N}}\ +{hat{gamma }}_{f}{hat{I}}_{f}-{hat{S}}_{f}{beta }_{ff}{bar{I}}_{f}-{hat{S}}_{f}{beta }_{fm}{bar{I}}_{m}-mu bar{N}{hat{S}}_{f}$$

(5a)

$$frac{d{hat{I}}_{f}}{dt}= frac{frac{b({hat{gamma }}_{f},{gamma }_{m})}{2}v{hat{I}}_{f}({bar{S}}_{m}+{bar{I}}_{m})+frac{b({gamma }_{f},{hat{gamma }}_{m})}{2}v{bar{I}}_{f}({hat{S}}_{m}+{hat{I}}_{m})}{bar{N}}\ +{hat{S}}_{f}{beta }_{ff}{bar{I}}_{f}+{hat{S}}_{f}{beta }_{fm}{bar{I}}_{m}-({hat{gamma }}_{f}+{alpha }_{f}+mu bar{N}){hat{I}}_{f}$$

(5b)

$$frac{d{hat{S}}_{m}}{dt}= frac{frac{b({hat{gamma }}_{f},{gamma }_{m})}{2}({hat{S}}_{f}+(1-v){hat{I}}_{f})({bar{S}}_{m}+{bar{I}}_{m})+frac{b({gamma }_{f},{hat{gamma }}_{m})}{2}({bar{S}}_{f}+(1-v){bar{I}}_{f})({hat{S}}_{m}+{hat{I}}_{m})}{bar{N}}\ +{hat{gamma }}_{m}{hat{I}}_{m}-{hat{S}}_{m}{beta }_{mf}{bar{I}}_{f}-{hat{S}}_{m}{beta }_{mm}{bar{I}}_{m}-mu bar{N}{hat{S}}_{m}$$

(5c)

$$frac{d{hat{I}}_{m}}{dt}= frac{frac{b({hat{gamma }}_{f},{gamma }_{m})}{2}v{hat{I}}_{f}({bar{S}}_{m}+{bar{I}}_{m})+frac{b({gamma }_{f},{hat{gamma }}_{m})}{2}v{bar{I}}_{f}({hat{S}}_{m}+{hat{I}}_{m})}{bar{N}}\ +{hat{S}}_{m}{beta }_{mf}{bar{I}}_{f}+{hat{S}}_{m}{beta }_{mm}{bar{I}}_{m}-({hat{gamma }}_{m}+{alpha }_{m}+mu bar{N}){hat{I}}_{m}.$$

(5d)

The birth terms in the preceding system of equations reflect (a) the fact that the mutant host, while it is rare, mates only homozygous resident hosts and (b) only half of the matings between heterozygous mutants and homozygous residents result in mutant offspring. Since the dynamics described by (5) are linear, we can again measure fitness (this time for the host) using the dominant Lyapunov exponent. We summarise the relevant information contained in this exponent with the host fitness function ({W}_{gamma }({hat{gamma }}_{f},{hat{gamma }}_{m},{gamma }_{f},{gamma }_{m})), again using techniques outlined by ref. 55. In keeping with the description of pathogen evolution, we assert that the hosts i is increasing when (frac{partial {W}_{gamma }}{partial {gamma }_{i}}{left|right.}_{hat{gamma=gamma }}) is positive, and decreasing when this partial derivative is negative, where (hat{gamma }=gamma) is shorthand for ({hat{gamma }}_{i}={gamma }_{i}) for all i.

We want to identify where the action of selection takes the resident pathogen and host traits (i and i, respectively) in the long term. As mentioned above, the model is too complicated to support exact mathematical predictions. Consequently, our methods rely on numerical simulation implemented in Matlab57. All Matlab code is publicly available (see Code Availability).

The numerical simulation takes as its input a set of parameters and an initial estimate of the long-term result of selection on co-evolution of pathogen and host ({alpha }_{i}^{*}), and ({gamma }_{i}^{*}) for i=f, m. The estimate is updated by (i) finding the corresponding equilibrium solution to Equation (1) in a manner that verifies its asymptotic stability, (ii) using that equilibrium solution to estimate partial derivatives (frac{partial {W}_{alpha }}{partial {tilde{alpha }}_{i}}{left|right.}_{tilde{alpha=alpha }}) and (frac{partial {W}_{gamma }}{partial {hat{gamma }}_{i}}{left|right.}_{hat{gamma=gamma }}) for i=f, m, and finally (iii) incrementing or decrementing elements of the estimate following the sign of the appropriate partial derivative. Steps (i)(iii) are repeated until the absolute value of all partial derivatives is within a tolerance of zero. The result of the simulation is an estimate of the convergence stable58,59 co-evolutionary outcome, assuming f and m, and f and m can be adjusted independently. Importantly, this predicted co-evolutionary outcome also corresponds to a system in which the pathogen is established in a stable equilibrium population of hosts.

Finally, we verified numerically that the convergence-stable estimate corresponded to a two-dimensional evolutionarily stable result60 for pathogen and host, respectively. For this reason, we can also refer to predictions generated by our numerical simulation as a continuously stable state, in analogy to the definition established by ref. 61.

Further information on research design is available in theNature Research Reporting Summary linked to this article.

Continued here:
On maternity and the stronger immune response in women - Nature.com

Matt Kaeberlein is what you might call a dog person. He has grown up with dogs and describes his German shepherd, Dobby, as really special. But Dobby is 14 years oldaround 98 in dog years. Im very much seeing the aging process in him, says Kaeberlein, who studies aging at the University of Washington in Seattle.

Kaeberlein is co-director of the Dog Aging Project, an ambitious research effort to track the aging process of tens of thousands of companion dogs across the US. He is one of a handful of scientists on a mission to improve, delay, and possibly reverse that process to help them live longer, healthier lives.

But dogs are just the beginning. Because theyre a great model for humans, anti-aging or lifespan-extending drugs that work for dogs could eventually benefit people, too. In the meantime, attempts to prolong the life of pet dogs can help people get onboard with the idea of life extension in humans. Read the full story.

Jessica Hamzelou

The quest to show that biological sex matters in the immune system

For years, microbiologist Sabra Klein has painstakingly made the case that sexdefined by biological attributes such as our sex chromosomes, sex hormones, and reproductive tissuescan influence immune responses.

Through research in animal models and humans, Klein and others have shown how and why male and female immune systems respond differently to the flu virus, HIV, and certain cancer therapies, and why most women receive greater protection from vaccines but are also more likely to get severe asthma and autoimmune disorders (something that had been known but not attributed specifically to immune differences.)

In the 1990s, scientists often attributed such differences to gender rather than sexto norms, roles, relationships, behaviors, and other sociocultural factors as opposed to biological differences in the immune system. Klein has helped spearhead a shift in immunology, a field that long thought sex differences didnt matterand shes set her sights on pushing the field of sex differences even futher. Read the full story.

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Extending dogs' lives, and sex and the immune system - MIT Technology Review

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Your Immune System Will Thrive With This Elderberry Hill Liquid Morning Multivitamin - Men's Journal

Prioritizing your health has never been more important. As COVID cases continue to spike and the monkeypox outbreak has now become a public health emergency, having a strong immune system is essential. Daily habits can impact our immune health and lifestyle choices such as smoking, poor diet, and too much alcohol consumption can weaken your immunity. But there are ways to help strengthen our body and knowing the signs of a troubled immune system is a start. Eat This, Not That! Health spoke with Dr. Tom Yadegar, Pulmonologist and Medical Director of the Intensive Care Unit at Providence Cedars-Sinai Tarzana Medical Center who shares what to know about your immune system and warning signals it's not as healthy as it should be. Read onand to ensure your health and the health of others, don't miss these Sure Signs You've Already Had COVID.

Dr. Yadegar states, "The immune system is the defender of the body. Composed of two arms, innate and adaptive, the innate system is a nonspecific response that fights any type of foreign invader that comes into contact with the body. This arm is generally the same in most people and is composed of white cells. The second arm, known as the adaptive immune system, is specific to the foreign invader and targets it using antibodies from previous infections or vaccines."

"When exposed to a foreign invader, the immune system creates antibodies in response to prevent severe symptoms in case of repeated exposure," says Dr. Yadegar. "When this process turns against healthy tissue instead of foreign pathogens, the immune system attacks the body, leading to an autoimmune state."

Dr. Yadegar shares, "Getting proper sleep, nutrition and regular exercise is a hallmark to keeping the immune system functional. Adequate vitamin intake, including vitamin C and vitamin D, is also important in ensuring a strong immune system. Patients who may have immunodeficiency, such as IgG deficiency, can also receive infusions to help keep their immune system healthy."

Dr. Yadegar tells us, "Fighting infections requires a lot of energy. When the body is depleted of its normal energy level, the immune system is weakened and can become susceptible to opportunistic infections. People generally feel this when they are tired. Ensuring a schedule of restful sleep, eating a balanced diet with fruits and vegetables and drinking enough water helps ensure your immune system is ready to answer the call of an infection."6254a4d1642c605c54bf1cab17d50f1e

According to Dr. Yadegar, "Infections that require multiple courses of antibiotics within a year may be a sign of a weakened immune system that is not able to fight off pathogens. Patients should be evaluated by their healthcare provider in order to further investigate the underlying cause."

"Normal wounds require the immune system to bring nutrients to repair damaged tissue," says Dr. Yadegar. "When this process is compromised, wounds are unable to heal properly, which signals a slow immune system. Delayed wound healing is indicative of a poorly-functional immune system, and should be evaluated by a healthcare provider."

Dr. Yadegar explains, "Long-term stress compromises the body's natural immunity, which can lead to higher risk of infections. While stress is inevitable in our fast-paced lives, taking steps to mediate stress can help. Whether meditation, exercise, or deep-breathing, it's important to tailor stress-relief to the individual in order to best improve their stress levels."

Heather Newgen

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Sure Signs Your Immune System Isn't as Strong as it Should Be Eat This Not That - Eat This, Not That