Rich Hill is trying different ways to make hitters uncomfortable while contributing to a team that has high expectations this season.

That part hasn't been perfect, but the 40-year-old Twins lefthander is coming off an outing on Sunday against Detroit during which he held the Tigers to two runs over five innings and left the game leading 5-2 before the bullpen had a rare multiplayer meltdown.

The fact that the oldest pitcher is baseball is even able take the mound this season is an achievement. Faced with Tommy John elbow surgery last October that threatened to knock him out for all of 2020, Hill ended up being a candidate for different type of elbow surgery that got him back on a mound in nine months.

"Absolutely pleased with my elbow," Hill said. "Feeling zero issues the entire time through rehab, through the throwing program, through any outing this season. The elbow has been great.

"Continue to keep moving in that upward fashion, and again, it's the four days in between, making sure that I'm getting in the work that I need to get in. The training staff has done a great job.

Instead of having Tommy John surgery, in which the ulnar collateral ligament is reconstructed using a ligament from a patient's forearm or hamstring and can knock a pitcher out of action for up to 16 months, a procedure called primary repair was used to strengthen the ligament instead of replacing it. A piece of tape that is coated with collagen is attached to the ligament and bone to assist in the repair and strengthening of the area. It is a less invasive surgery than the one named after John, the pitcher who was the first to have such a surgery in 1974. Therefore, the recovery time is shorter.

Making the call

Given his age and desire to chase a World Series, Hill was all ears once he learned of the possibility of the surgery. He spent nearly three months on the Los Angeles Dodgers' injured list last season because of a left forearm strain and still had trouble upon his return.

But the primary repair surgery is still relatively new, going back to 2011, in comparison to hundreds of Tommy John surgeries being performed since 1974. Only a handful of baseball players, including pitchers Seth Maness and Jesse Hahn and outfielder Brandon Guyer, have had the procedure. Hill consulted with several of the nation's top orthopedic surgeons including James Andrews, Neal El-Attrache and Timothy Kremchek to learn as much as he could about the procedure. He also spoke with Maness and Guyer.

"I gathered as much information as I could talked to maybe every major orthopedic surgeon in baseball," Hill said. "I think I talked to everyone across the country as far as orthos go. Understanding this has been a very successful surgery and I wanted to make sure the percentages were going in the right direction as far coming back as possible and making sure I would not be looking back and having something."

Unique case

Still, he had to be the right candidate for the procedure. Each UCL tear is different. If the tear is in the middle of the ligament, the tape might not be effective. A tear off the bone is considered the perfect candidate for primary repair.

And a surgeon will not know if a ligament can be treated with primary repair until after he or she can open up the damaged area and inspect the ligament. A Magnetic Resonance Imaging exam isn't enough.

"You can't look at it and say 'I want that one,'" said Dr. Jeffrey Dugas of the Andrews Sports and Orthopedic Center in Birmingham, Ala. "You've got to fit the mold for it. You have to have the right tissue, the right injury and that doesn't occur all the time. There are lots of people who still are better off with reconstruction."

Tissue issues

Dugas who performed the surgery on Hill, who previously had Tommy John surgery in 2011. Dugas took a look at the damage and determined primary repair was the way to go.

"Rich had previous reconstruction, so he had already had Tommy John surgery," Dugas said. "So he had more tissue than the average person who had never torn it before. He had his own tissue plus the graft. He had a ton of tissue to deal with.

"He had double or triple the amount of tissue."

On top of it all, Hill also underwent a stem cell injection, with the stem cells coming from his own bone marrow, to assist in the healing process. Hill stopped at nothing to get back on the mound this season.

Ups and downs

On New Year's Eve, he signed with the Twins, getting a contract worth $3 million with bonuses for games started and innings pitched, with both sides understanding he wouldn't be ready until July. As it turned out, that's when the truncated season started, cutting Hill's base salary to $1.1 million in a 60-game season.

After his first start, he missed three weeks because of shoulder fatigue, working at St. Paul to get back in the Twins' rotation. In five starts, he is 1-1 with a 3.86 ERA. He's been knocked out in the third and fourth innings in two of his outings, and opponents' line drive percentage of .290 is the highest against Hill in his career.

But Hill has spent his 16-year career adapting, being used as a starter with the Cubs, to being a reliever with the Red Sox, to being a starter again with the Dodgers and now with the Twins. And there was a stop in independent ball when things weren't working out for him.

Adding a pitch

Everyone knows Hill throws plenty of curveballs, a pitch he can change the shape of and speed. But he's broken out a cut fastball lately, throwing 18 over his last three starts. It's something else for hitters to think about and a pitch that could help him down the stretch in the heat of a pennant race.

Because that's what it was all about for Hill, getting healthy as fast as possible and getting another chance at the postseason while he still can.

"The last five years have just been an incredible experience of just being able to use that knowledge to now, where my body is strong and healthy again, to be able to continue to use that knowledge," Hill said, "and to ultimately it is to win a World Series and that's the biggest thing.

"Am I chasing a World Series? Yeah I am, and everyone here is chasing a World Series."

About Rich Hill

Age: 40

Size: 6-5, 220

Position: lefthanded starting pitcher

Hometown: Milton, Mass.

College: Michigan

Drafted: Reds, 36th round, 1999; Angels, seventh round, 2001; Cubs, fourth round, 2002 (signed).

Major league teams: Cubs (2005-08), Orioles (2009), Red Sox (2010-12, 2015), Indians (2013), Angels (2014), Yankees (2014), Oakland (2016), Dodgers (2016-2019), Twins (2020).

Career stats: 16 seasons, 289 games, 161 starts, 66-43, 3.82 ERA. In 10 postseason series, 13 games, 1-2, 3.06 ERA.

Oh, no! Hill had a no-hitter going in the 10th inning of a 2017 game that was ruined by a walk-off home run by Pittsburgh's Josh Harrison.

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Complicated elbow repair has Twins' Rich Hill back on the mound - Minneapolis Star Tribune

Bone Marrow Stem Cells Comments Off on Complicated elbow repair has Twins’ Rich Hill back on the mound – Minneapolis Star Tribune | September 9th, 2020

Three years after retiring from the BC Forest Service in 2013,Bob Trudeau of Kamloops began experiencing extreme pain in his torso while out on his regular trail runs and backpacking treks in the area around his hometown

A fit, avid outdoorsman who followed a healthy and active lifestyle, Trudeau was concerned and decided to see his doctor. After a series of tests, he was dumbfounded to learn that the pain was the result of 11 fractured vertebrae a common symptom of the disease with which he would soon be diagnosed.

A few weeks later, on Jan. 3, 2017, Trudeau, then 59, was even more stunned when he received the diagnosis of multiple myeloma, a little-known and incurable cancer of the plasma cells.

It was like, Happy New Year, youve got myeloma, Trudeau said. To suddenly find out that I had an incurable cancer that Id never heard of was unbelievable. Ive always led a very active and healthy life. I just couldnt understand it. I was shocked.

Shortly after his diagnosis, Trudeau underwent intense chemotherapy in preparation for a stem cell transplant in August 2017 The transplant was a success he was in remission. Unfortunately, 18 months later, the myeloma resurfaced and he had to find another treatment regimen to keep the cancer in check.

Today, Trudeaus condition is stable and he is on a maintenance program consisting of a combination of immunotherapy and chemotherapy drugs.

Trudeau, who has returned to running, is co-leading the Kamloops Myeloma Support Group.

My wife, Jennifer and I have been wanting grandchildren for years and now it's happening! he said. We're very much enjoying little Jacob and being able to help our daughter.

Trudeau and his family will be raising funds for myeloma research and awareness of the disease when they take part in the fourthannual Kamloops Multiple Myeloma March, which will take place on Sunday, Sept. 13, at 9 a.m.

This years event has been modified to help stop the spread of COVID-19. In compliance with physical-distancing measures, participants are encouraged to hold their own walk in their neighbourhood at the same time as the regularly scheduled march onSept. 13. Trudeau plans to run and walk 50 kilometres on a trail he has mapped out around Kamloops.

Local participants have set their fundraising goal at $10,000. The national fundraising goal is set at $650,000.

The Multiple Myeloma March is now in its 12thyear. The annual five-kilometre event brings Canadian communities together to raise funds for research and to help improve the lives of those impacted by myeloma. Kamloops is one of a record 33 communities across the country to be included in this years event. Information can be found by clicking here.

Multiple myeloma, also known as myeloma, is thesecond-most common form of blood cancer. Myeloma affects a type of immune cell called the plasma cell, found in the bone marrow. Every day, nine Canadians are diagnosed, yet in spite of its growing prevalence, the disease remains relatively unknown.

While there is no cure, people with myeloma are living longer and better lives, thanks to recent breakthroughs in treatment. To learn more, or to donate, visitwww.myeloma.ca.

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Annual Kamloops Multiple Myeloma March to be held on Sept. 13 - Kamloops This Week

Bone Marrow Stem Cells Comments Off on Annual Kamloops Multiple Myeloma March to be held on Sept. 13 – Kamloops This Week | September 9th, 2020

INTRODUCTION

Articular cartilage is an elastic connective tissue in the joint (1). Cartilage injury is extremely common, yet cartilage has limited self-healing capacity because of its low cellularity and avascular nature. Because damage to cartilage leads to knee joint dysfunction, resulting in substantial pain and disability in the arthritic joint, cartilage or joint reconstruction remains a considerable challenge.(1). Arthritic joints in clinical practice are replaced by total joint arthroplasty using metallic and synthetic prosthesis (2, 3). Existing joint prostheses do not remodel with host joint tissue and can lead to long-term failure by aseptic loosening or infection (4), which could only be addressed by biological regeneration of the joint. Recently, using mesenchymal stem cell (MSC) transplants and then stimulating the directional differentiation into chondrocytes is becoming the method of choice for cartilage repair (5, 6). Clinical studies have shown that joint cartilage damage always extends deeply into the subchondral bone and, thus, causes osteochondral defects in the knee joint, which can alter the joints biomechanical properties and influence the long-term performance of the cartilage tissue (7), indicating the significance of simultaneous repair of whole-layer anisotropic articular cartilage in successful knee repair. As articular cartilage transitions from the superficial zone to the deep zone, the extracellular matrix (ECM) of the cartilage is characterized by increased oxygen tension and nutrient availability, lower amounts of ECM constituents such as glycosaminoglycans (GAG), and increased presence of a different phenotype of chondrocyte population with hypertrophic and ossification markers such as RUNX2 (Runt-related transcription factor 2) and type X collagen (8, 9). The gradient and anisotropic structure in ECM deposition and cell type provides excellent permeability in deep zone (vessel ingrowth) as well as desired mechanical support (10). However, developing biomimetic constructs mimicking the gradient anisotropic structure and the signaling approaches in different layers to induce zonal-dependent chondrogenic differentiation and ECM deposition is very challenging in cartilage repair. Previous studies showed that scaffolds with small pore size (100 to 200 m) could better promote chondrogenesis in osteochondral regeneration (11). However, osteogenesis and angiogenesis were inhibited in these scaffolds with small pore sizes, showing less nutrient diffusion and worse tissue integration by decreased microvessel ingrowth in these scaffolds (12). Hydrogel has been reported for cartilage regeneration in many studies (13, 14), yet it is still difficult to construct large-scale tissue structures with hydrogel owing to inadequate structural integrity, mechanical stability, and printability (12). Here, we report developing three-dimensional (3D) bioprinted dual-factor releasing and gradient-structured MSC-laden constructs ready to implant for whole-layer cartilage regeneration.

Different joint tissue constructs for joint reconstruction were fabricated using 3D bioprinting as previously reported with organ printing united system (OPUS; Novaprint) (15). To better mimic the native cartilage, we incorporated biochemical stimulus (BCS) with different growth factor releasing, and biomechanical stimulus (BMS) with small pore sizes to induce better chondrogenesis to create the dual-factor releasing and gradient-structured cartilage construct in the double stimulus (DS) group. We chose to test the combination of bone morphogenetic protein 4 (BMP4) and transforming growth factor3 (TGF3) in the cartilage construct in an established knee cartilage defect model given its potential generalizability in the regeneration of complex, inhomogeneous joint tissues. Poly(lactic-co-glycolic acid) (PLGA) (50:50 PLA/PGA) microspheres (S) were used to deliver TGF3 and BMP4 in hydrogel (Fig. 1, A and B). Briefly, poly(-caprolactone) (PCL) was molten to fabricate the physically gradient supporting structure for the scaffold, while MSC-laden hydrogel encapsulating PLGA microparticles carrying TGF3 or BMP4 in different layers was bioprinted into the microchannels between PCL fibers from different syringes (fig. S1). During plotting, the needle diameter, layer thickness, and speed for PCL printing were kept constant at 200 m, 200 m, and 180 mm/min, respectively. The fiber spacing was kept constant at 150 m (BMS group) or 750 m (BCS group) for nongradient (NG) scaffolds and varied gradually from 150 to 750 m throughout the gradient scaffolds (DS group) (fig. S1). The gradient microchannels between PCL range gradually from 150 m wide from the superficial zone of the cartilage, providing enough mechanical properties and smaller compartments favoring articular chondrocyte differentiation (11, 16), to 750 m wide in the deepest zone of the cartilage construct, maximizing diffusion of nutrients with better microvessel ingrowth and offering higher oxygen stress in the deep zone (Fig. 1B) (12). The fiber spacing was changed by 200 m every millimeter. The scaffolds were plotted in blocks of 4 4 4 mm for rabbit cartilage construct and 14 14 14 mm for human cartilage construct (Fig. 2A and movie S1).

(A) Schematic Illustration of the study design with 3D bioprinted dual-factor releasing and gradient-structured MSC-laden constructs for articular cartilage regeneration in rabbits. Schematic diagram of construction of the anisotropic cartilage scaffold and study design. (B) A computer-aided design (CAD) model was used to design the four-layer gradient PCL scaffolding structure to offer BMS for anisotropic chondrogenic differentiation and nutrient supply in deep layers (left). Gradient anisotropic cartilage scaffold was constructed by one-step 3D bioprinting gradient polymeric scaffolding structure and dual protein-releasing composite hydrogels with bioinks encapsulating BMSCs with BMP4 or TGF3 S as BCS for chondrogenesis (middle). The anisotropic cartilage construct provides structural support and sustained release of BMSCs and differentiative proteins for biomimetic regeneration of the anisotropic articular cartilage when transplanted in the animal model (right). Different components in the diagram are depicted at the bottom. HA, hyaluronic acid.

(A) Gross appearance of (a) human-scale and (b and c) rabbit-scale cartilage scaffold (b, NG with 150-m spacing; c, NG with 750-m spacing). Top view of the rabbit cartilage scaffold is also shown (d, NG with 150-m spacing; e, NG with 750-m spacing; f, gradient scaffold with 150- to 750-m spacing) atop of the SEM images (g, horizontal section; h, vertical section) taken for the 150-m NG scaffold to demonstrate the precise alignment of the PCL fibers in the printed scaffold. (B) Deconstruction of the gradient scaffold. The structure of the gradient scaffold was deconstructed into four layers. Microscopic appearance of the hydrogel-PCL composite structure in each layer demonstrated good interconnectivity and delicate, orderly aligned structure for each layer. (C and D) Good cell viability is shown respectively for superficial and deep layers after printing with live/dead assay (green, live cells; red, dead cells) (C) under a microscope and (D) under a confocal microscope. DAPI, 4,6-diamidino-2-phenylindole. (E) Cell spreading in superficial and deep layers with cytoskeleton staining. (F) Immunostaining for cartilage markers in superficial and deep layers. Expression of COL2A1 and PRG4, the lubrication markers, was significantly higher in the superficial layers with small pore size (a and b), while the chondrogenic cells in the deep layers (c and d) mostly presented with hypertrophic phenotype (COL10A1 expression). Photo credit: Ye Sun, First Affiliated Hospital of Nanjing Medical University.

Recombinant human TGF3 (rhTGF3) and rhBMP4 were microencapsulated in PLGA S (fig. S1) (17). TGF3 and BMP4 S were mixed in the cell-laden hydrogel (table S1), respectively, and printed into the microchannels between PCL fibers with different syringes (Fig. 2B and fig. S1). To chemically simulate the hypertrophic layer in native cartilage, we used PLGABMP4-encapsulated MSC-laden hydrogel in the deepest layer with a 750-m PCL fiber spacing, while PLGATGF3 was used for the other three layers of the cartilage construct. Scanning electron microscopy (SEM) images of PLGA S were taken, showing a less than 2-m diameter for most of the PLGA S. The PLGA-encapsulated MSC-laden hydrogel also showed nice printability as demonstrated (Fig. 2B and fig. S1A).

The final product of the human and rabbit cartilage construct demonstrated good interconnectivity and delicate, orderly aligned structure under the microscope, SEM, and in gross appearance for both PCL fibers and the printed hydrogel in between (Fig. 2, B to D). To validate S distribution in MSC-laden hydrogel, fluorophore-conjugated rhodamine was encapsulated into PLGA S and delivered to the hydrogel. At day 7, PLGArhodamine S showed well-proportioned distribution and minimal cell toxicity in the hydrogel printed between the PCL fibers under a confocal microscope (Fig. 2, C and D, and fig. S1B). Immunostaining for cartilage markers in the gradient scaffold was performed (Fig. 2, E and F). Resembling the native cartilage, the expression of COL2A1 (Collagen Type II Alpha 1 Chain) and PRG4 (Proteoglycan 4), the lubrication marker, was significantly higher in the superficial layers with small pore size, while the chondrogenic cells in the deep layers mostly presented with hypertrophic phenotype (COL10A1 expression) (Fig. 2F and fig. S2). Moreover, the compressive Youngs modulus of the NG-150 scaffold and the gradient scaffold were similar to that of the native cartilage and significantly higher than that of the NG-750 scaffold (fig. S3), demonstrating that smaller PCL fiber spacing plays an important role in enhancing the mechanical properties of the PCL-hydrogel composite scaffolds. In biomimetic regeneration of native articular cartilage, the gradient scaffold could provide anisotropic chondrogenesis in different layers and structural support for the newly formed cartilage tissue in compression, and allow nutrient supply and vessel ingrowth in the deep layers.

To examine the effects of BMP4, TGF3, and their S on bone marrow stromal cell (BMSC) viability and proliferation, we cultured BMSCs in the composite hydrogel for 7 days (fig. S4). Spheres showed controlled release of TGF3 first, followed by BMP4. Relatively rapid TGF3 release in the three layers with smaller PCL fiber spacing and slower release of BMP4 in the deepest layer were sustained over 60 days in vitro (fig. S5). Similar viability and proliferation rate of BMSCs were demonstrated for BMP4 and TGF3 compared with control through 7 days in the hydrogel (fig. S4, A, C, and D). Compared with empty S, S encapsulating BMP4 and TGF3 also showed minimal toxicity to BMSC viability and proliferation in the hydrogel (fig. S4, B, E, and F). Cell viability and proliferation were further examined in the printed scaffolds (Fig. 3, A to E). Scaffold fabrication with gradient structure (Fig. 3A, left) and delicate alignment of hydrogel printing (Fig. 3A, right) were separately conducted. Printed cell-laden hydrogel causes cell alignment in a longitudinal direction of the printed paths, forming a reticular network with cell interaction (Fig. 3B). The PCL pillar structure in the final construct further stabilized the 3D printed BMSC organization, inducing a compaction phenomenon of the patterns of cell alignment in the cell-laden hydrogel (Fig. 3C). Survival of BMSCs throughout the final cartilage construct with gradient structure was examined at 60 min (day 0), 1 day, 7 days, and 21 days after printing (Fig. 3, I to K). Live/dead cell assays showed 95% cell viability on day 0, which was maintained over 75% through days 3 to 21 (Fig. 3D). Cell proliferation, assessed using the alamarBlue assay system, increased over a 21-day period, similar to the proliferation of control cells encapsulated in a fibrin construct (Fig. 3E). Immunostaining of cytoskeleton showed cell spreading, both in the hydrogel and the PCL fibers throughout the four layers of the construct (Fig. 3C). At day 21, good 3D anchoring to the PCL fiber cylinder was observed for the BMSCs released from the hydrogel (Fig. 3F). These data indicate that the one-step 3D bioprinted dual-factor releasing and gradient-structurally optimized cartilage scaffold preserved cell viability during the printing process and provided a favorable microenvironment for BMSC proliferation, spreading, and condensation for differentiation into chondrocytes in vitro.

(A) Schematic of anisotropic cartilage scaffold construction with fabrication of gradient scaffolding structure (left) and large-scale printing of aligned protein-releasing BMSC-laden hydrogel (right). Scale bar, 1 mm. (B) Gross appearance of PLGA Sencapsulated BMSC-laden hydrogel under a microscope (top). Printed cell-laden hydrogel causes cell alignment in a longitudinal direction of the printed paths, forming a reticular network with cell interaction (bottom). (C) Live/dead cell assays showed 95% cell viability maintained through day 1 to 21 for all four layers with gradient spacing (4th row, 150-m spacing; 3rd row, 350-m spacing; 2nd row, 550-m spacing; 1st row, 750-m spacing). Immunostaining of cytoskeleton (rightmost column) showed cell spreading both in the hydrogel and on the PCL fibers throughout the four layers of the construct. Scale bar, 500 m. (D and E) Quantified cell viability and proliferation in the printed scaffolds. (F) Cell anchoring in the scaffolds. (a to c) At day 21, good 3D anchoring to the PCL fiber cylinder was observed for the MSC cells released from the hydrogel. (d to f) Similar cell anchoring was observed for PCL fibers in adjacent layers. (b), (c), (e), and (f) are 3D demonstration of cell anchoring in (a) and (d), respectively. Scale bars, 100 m. Photo credit: Ye Sun, First Affiliated Hospital of Nanjing Medical University.

Before in vivo application of the scaffold, we ascertained whether spatiotemporal delivery of rhTGF3 and rhBMP4 induced layer-specific BMSC differentiation into chondrocytes that present with hyaline articular and hypertrophic phenotype. Articular chondrocytes with hyaline and hypertrophic phenotype were first derived from rabbit BMSCs in vitro. Hyaline chondrocytes concurrently produced both aggrecan and type II collagens, while hypertrophic chondrocytes produced type I collagen and type X collagen. Sequential application of rhTGF3 for 2 weeks in culture, followed by rhTGF3 for another 4 weeks (TGF3 group), induced differentiation of BMSCs into chondrocytes that synthesized aggrecan and type II collagens, suggesting hyaline articular chondrocyte-like cells. BMSCs sequentially treated with rhTGF3 and rhBMP4 demonstrated significantly higher type I collagen, type X collagen, and aggrecan protein expressions than the control (Fig. 4A and fig. S6). Moreover, cells in the TGF3-induced tissue were fibroblastic, whereas those induced with BMP4 were larger and arranged in a cobblestone pattern (Fig. 4A), similar to hypertrophic chondrocytes previously generated in culture (5). Condensation of BMSCs that indicated differentiation was observed at 4 weeks (fig. S6B). Both treatments induced BMSC differentiation and yielded a cartilaginous matrix that stained positively for toluidine blue and alcian blue in condensed BMSCs, indicative of a proteoglycan-rich, cartilage-like ECM.

(A) Chondrogenic differentiation of condensed rMSCs with toluidine blue (TB) and alcian blue (AB) staining. (B) Scaffolds were transplanted subcutaneously for 12 weeks. (C) To validate the cartilage-generating capability, scaffolds were incubated and observed for 12 weeks in vitro, indicating better cartilage-generating potential for the physically gradient protein-releasing scaffold (movie S2). (D) Youngs modulus of the scaffolds compared with native cartilage after 12 weeks. Data are presented as averages SD (n = 6). *P < 0.05 between the NG-750 group and other groups; #P < 0.05 between the native cartilage group and other groups. (E) In the generated cartilage tissues, spatiotemporally released dual-factors induced zone-specific expression of PRG4, aggrecan, and collagens II and X and showed resemblance with native joint cartilage. (F) (a to c) Toluidine blue staining of the 3D printed cartilage constructs (a, top view; b, side view; c, bottom view) after culture in chondrogenic medium for 6 weeks in vitro. (d to g) Toluidine blue and (h to k) alcian blue staining was applied for each layer of the gradient scaffold. (l to p) Safranin O (SO) and (q to t) toluidine blue staining of cartilage tissue between PCL fibers (green curved line) in different layers of the 3D printed cartilage constructs after subcutaneous implantation. Photo credit: Ye Sun, First Affiliated Hospital of Nanjing Medical University.

Cartilage scaffolds incorporating rhTGF3 and rhBMP4 for spatiotemporally controlled release were also examined in different groups of scaffolds transplanted in vivo subcutaneously for 12 weeks (Fig. 4, B to F). To validate the cartilage-generating capability of the composite scaffold, the protein-carrying scaffolds were incubated and observed for 12 weeks in vitro (Fig. 4C). All scaffolds, physically gradient or NG, showed cartilage-like tissue development surrounding the scaffolds, whereas the BCS and BMS scaffolds developed 1/4 to 1/3 thickness cartilage tissue, while the DS scaffold showed almost full-thickness coverage of cartilage-like tissue around the construct (movie S2), indicating a significantly better cartilage-generating potential in vitro and a better prospect of its cartilage matrix integration in vivo for the physically gradient protein-releasing scaffold (Fig. 4C). The compressive Youngs modulus of the BMS scaffold and the DS scaffold were similar to that of the native cartilage and significantly higher than that of the BCS scaffold with large pore sizes (Fig. 4D), demonstrating that smaller PCL fiber spacing plays an important role in enhancing the mechanical properties of the PCL-hydrogel composite scaffolds. The enhanced mechanical properties are promising for biomimetic regeneration of native articular cartilage and provide structural support for the newly formed cartilage tissue.

After 12 weeks in vivo, spatiotemporally released rhTGF3 and rhBMP4 in the DS scaffold induced zone-specific expression of PRG4, aggrecan, and collagen II and X assayed with immunofluorescence, showing resemblance with native joint cartilage (Fig. 4E). Superficial zone marker PRG4, with a gradient manner throughout the four layers, was presented mainly in the superficial layer with the smallest PCL compartments (Fig. 4E, first column, 150 m 150 m). Abundant cartilaginous matrix with collagen type II and aggrecan was present in a gradient manner primarily in the superficial layers with TGF3 delivery, whereas hypertrophic marker collagen type X was primarily expressed in the deepest zone (Fig. 4E, second to fourth columns). Cartilaginous matrix was demonstrated and stained positive for toluidine blue for the scaffold (Fig. 4F, a to c). To determine the production of GAG in each layer of the gradient scaffold, we applied toluidine blue staining (Fig. 4F, d to g) and alcian blue staining (Fig. 4F, h to k). The whole gradient scaffold body stained positive (Fig. 4F, a to c), with a gradient staining intensity from the superficial layer to the deepest layer (Fig. 4F, d to k), indicating a gradient cartilaginous matrix formation resembling the native cartilage matrix. Safranin O staining and toluidine blue staining of the generated cartilage tissue sections showed the production of a cartilaginous matrix between PCL fibers in different layers of the 3D printed cartilage constructs after subcutaneous implantation in vivo (Fig. 4F, j to s). The chondrocytes in the newly formed tissue demonstrated similar morphological characteristics to those in native cartilage. A large fraction of generated chondrocytes in the TGF3-induced tissue were fibroblastic, whereas those induced with BMP4 in the deepest layers were larger and arranged in a cobblestone pattern, similar to hypertrophic chondrocytes generated in the culture plate (Fig. 4F, l to t). All cells located within typical chondrocyte lacunae, surrounded by cartilaginous matrix.

Rabbits were used as animal models to evaluate the knee repair capacity of the cartilage scaffolds. Cartilage scaffolds were constructed by one-step 3D bioprinting gradient polymeric supporting structure and different protein-releasing composite hydrogels with bioinks encapsulating BMSCs with BMP4 or TGF3, providing structural support and sustained release of BMSCs and differentiative proteins for biomimetic regeneration of the native articular cartilage (Fig. 5). As shown in Fig. 5A (first row), a full-thickness cartilage defect was created in the knee joint. The scaffold was implanted into the defect to test for cartilage tissue regeneration. Cartilage repair with the DS scaffold showed much better gross appearance at 8, 12, and 24 weeks compared with the BCS and BMS scaffolds (Fig. 5A, second to fourth rows). During the 24-week posttransplantation period, magnetic resonance imaging (MRI) was made for the operated knee joint, demonstrating significantly better resolution of subchondral edema and healing of the articular surface after 24 weeks for the DS group (Fig. 5A, fifth row). In addition, the chondroprotective effects of the scaffolds were compared (18). The gradient scaffold group showed better chondroprotective effects with a significantly higher histological grading compared with the NG groups over the 24 weeks in vivo (Fig. 5, B to E). Better repairing effects were demonstrated with gradient scaffolds compared with NG groups over 24 weeks (Fig. 5, B to E). Compared with the control group, the gradient group also showed better cartilage regeneration capabilities (fig. S7) and chondroprotection with significantly minor damage to the femoral condyle and tibial plateau (Fig. 5, D and E). Examination of intra-articular inflammatory response showed no significant difference in interleukin-1 and tumor necrosis factor level among different groups, maintaining at a relatively low level during the 24-week cartilage healing (fig. S8, A and B, and table S2). After the 24-week healing, histomorphological analysis was conducted for the generated cartilage. As shown in Fig. 5B, the DS scaffold regenerated fully hyaline-like cartilage in the defect site as evidenced by intense staining for GAGs and better cell filling in hematoxylin and eosin (H&E) staining (Fig. 5B). Type 1 and III collagens were also demonstrated in the regenerated cartilage with picrosirius red staining and compared with the native cartilage (Fig. 5B). Immunohistochemical staining of markers (PRG4 and type II and X collagens) for chondrocyte phenotype was conducted in the generated cartilage tissue sections in different groups compared with the native cartilage (fig. S8C). In the superficial zone, only the DS scaffolds showed PRG4 staining in the superficial chondrocytes in the generated cartilage tissue. Meanwhile, gradient expression of type II and X collagens, resembling the native cartilage, was also demonstrated from the superficial zone to the deep zone of the newly formed cartilage in the DS group, indicating successful construction of the anisotropic layered cartilage with different chondrocyte phenotypes and gradient ECM deposition by the 3D bioprinted dual-factor releasing and gradient-structured MSC-laden scaffold. Furthermore, neocartilage in the DS group showed more similar appearance to normal cartilage than other groups (Fig. 5B and fig. S8C). The above results indicated that the DS anisotropic scaffold had a better cartilage-repairing effect than the BCS or BMS groups and maintained better joint function after transplantation.

(A) Scaffold implantation process and gross appearance of the repair cartilage at 8, 12, and 24 weeks. MRI was made for the operated knee joint (fifth row), demonstrating significant better resolution of subchondral edema and healing of the articular surface (white arrowheads) for joint transplanted with DS scaffolds. (B to F) Chondroprotective effects of the scaffolds were compared by (B) histological scoring evaluation of the repaired cartilage tissue during in vivo implantation. (C) Mankin score and (D) ICRS (International Cartilage Repair Society) histological score of articular cartilage in the femoral condyle (FC) and tibial plateau (TP) in both groups with scaffold implantation. *P < 0.05 between the native group and other groups. #P < 0.05 between the BCS group and the DS group. Data are presented as averages SD (N = 6). (A) Histomorphological analysis of the neocartilage tissue at 24 weeks. PR, picrosirius red. The left bottom panels are higher-resolution pictures of the formed neocartilage outline in the colored square boxes. (a to e) Sections were stained with (a) H&E, (b) Safranin O, (c) TB, and (d) AB staining to indicate the presence of proteoglycans in different groups compared with native cartilage. (e) Picrosirius red was used to stain collagens I and III. The brown irregular area at the interface under the formed neocartilage was undegraded PCL material as supporting structure for the scaffolds. Photo credit: Ye Sun, First Affiliated Hospital of Nanjing Medical University.

As native articular cartilage transitions from the superficial zone to the deep zone, different phenotypes of chondrocyte population were presented with higher lubrication and GAGs (PRG4, ACAN expression) in the superficial layers and ossification (RUNX2, COL10A1 expression) in the deep layers. In the present study, we further tested the anisotropic properties of the generated cartilage and compared it with the native cartilage. In the superficial layer, immunostaining demonstrated greater PRG4 and ACAN expression in the DS group and the native cartilage compared with other two groups (Fig. 6, A to C). Meanwhile, higher expression of ossification markers (RUNX2 and COL10A1) were also observed for the group with implanted dual-factor releasing and gradient-structured scaffold (Fig. 6, D to F). These results indicate that the dual-factor releasing and gradient-structured scaffold could better restore the anisotropic properties of the native cartilage with different chondrogenic and ossification markers in specific layers. Moreover, resembling the ingrown microvessels in the deep layers of the native cartilage, the DS scaffold could better promote microvessel ingrowth compared with the group with small pore sizes, indicating better nutrient supply and tissue integration with large pore sizes in the deep zone (Fig. 6, G and H).

(A to C) In the superficial layer, immunostaining demonstrated greater PRG4 and ACAN expression in the DS group and the native cartilage compared with other two groups. (D to F) Meanwhile, higher expression of ossification markers (RUNX2 and COL10A1) were also observed for the group with implanted dual-factor releasing and gradient-structured scaffold in deep layers. (G and H) Moreover, the DS scaffold could better promote microvessel ingrowth compared with the group with small pore sizes, indicating better nutrient supply and tissue integration with large pore sizes in the deep zone. *P < 0.05 between the native group and other groups. #P < 0.05 between the DS group and other groups. BC, biochemical stimulus; BS, biomechanical stimulus. **P < 0.01; ##P < 0.01.

In conclusion, we have generated 3D bioprinted anisotropic constructs with structural integrity for joint reconstruction and articular cartilage regeneration and further tested the functional knee articular cartilage construct in a rabbit cartilage defect model with 6-month follow-up. Human-scale cartilage constructs with the structural integrity needed and that are ready for surgical implantation were created by sequentially printing protein-releasing and MSC-laden hydrogels with synthetic PCL polymer with gradient structures, a technique that could also be applied to the regeneration of the whole joint. In previous studies, relative nonuniformity was possible when hydrogel was printed alone without PCL as scaffolding support. Although hydrogel could serve as a carrier of cells and growth factors, it alone was quite not suitable for construction of complex biomimetic tissues with required mechanical properties. The combined printing with PCL scaffolding offered the uniformity for the hydrogel and the mechanical properties needed for in vivo study. In the present study, the cell-laden hydrogel allows well-proportioned distribution of MSCs and the protein-encapsulated S and thus protects cell viability and promotes its differentiation and expansion in the scaffold (17). Meanwhile, the adjacent PCL scaffolding provides adequate mechanical support and architectural integrity, offering a stable microenvironment for the 3D anchored MSC cells within the hydrogel to differentiate and form the tissue with their secreted cartilage matrix that replaces the hydrogel as it slowly degrades (15).

However, the release of the growth factors from the embedded S was not tracked in vivo after the scaffold transplantation. The intra-articular environment in vivo would definitely lead to faster disintegration of the S in the hydrogel. In this case, the PCL scaffolding would offer a much more stable microenvironment for cell and growth factor release than hydrogel alone. Lineage tracing studies have provided compelling evidence that articular chondrocytes derive from interzone cells in regions of condensing chondrogenic mesenchyme (19), similar to our observations that the MSCs, in the presence of TGF3 and BMP4, condense in the small compartments with surrounding PCL fibers as supporting structure and develop into articular chondrocytes that express genes expressed in cartilage layers. The MSC-derived articular chondrocytes were able to generate and maintain stable cartilage phenotype in vivo when transplanted into the knee defect site. The ECM composition of TGF3- or BMP4-induced cartilage tissues in the bioprinted scaffold shared many characteristics of native articular cartilage, including the gradient expression of type II collagen, superficial localization of PRG4, and abundant presence of type X collagen in the deep zone, indicative of regenerated superficial zone articular cartilage and deep zone hypertrophic cartilage in the constructs. In summary, we have generated 3D bioprinted constructs with structural integrity for joint reconstruction and articular cartilage regeneration and further tested the functional knee articular cartilage construct in a rabbit cartilage defect model with 6-month follow-up. Generating 3D bioprinted functional constructs as prosthesis for joint replacement or cartilage repair provides an opportunity to integrate the feasibility of MSC- and 3D bioprintingbased therapy for injured or degenerative joints. Evaluation will be needed to assess the function of the joint constructs in animal experiments and whether the functional cartilage phenotypes could be sustained in daily function. For translation, we envision the surgeons could incorporate surgery and 3D bioprinting by performing a mini-invasive arthroscopy procedure to replace the damaged or degenerated articular cartilage with 3D bioprinted cartilage scaffold or by performing joint replacement surgery using 3D bioprinted joint scaffolds.

BMSCs were isolated from rabbit bone marrow aspirates. Briefly, marrow aspirates (20-ml volume) were harvested and immediately transferred into plastic tubes. Isolated rMSCs were expanded in minimum essential medium containing fetal bovine serum (10%), d-glucose (4.5 mg/ml), nonessential amino acids (0.1 mM), sodium pyruvate (1 mM), Hepes buffer (100 mM), penicillin (100 Ul/ml), streptomycin (100 g/ml), and l-glutamate (0.29 mg/ml). Medium was changed twice a week, and rMSCs were used at passage 2 for the following experiments. TGF3 (10 ng/ml) was added in the medium for 2 weeks, and then TGF3 was replaced with BMP4 (50 ng/ml) in some of the cultures for another 4 weeks. Medium was also changed twice a week. Immunofluorescence staining of chondrogenic markers (Col1A1, Col2A1, Aggrecan, and Col10A1) was conducted to compare the generated chondrocyte phenotype and observed under confocal microscopy (Leica, Japan). The expression of chondrogenesis markers (SOX9, Col1A1, and Col2A1), superficial zone chondrocyte markers (ACAN, PRG4, CILP2, GDF5, and Col22A1), and deep zone chondrocyte markers(Col10A1, RUNX2, and ALP) after TGF3 or BMP4 incubation for 6 weeks was analyzed by real-time polymerase chain reaction (RT-PCR) using an ABI 7300 RT-PCR system (Applied Biosystems, USA). Six-week-old tissues generated under both conditions were stained with toluidine blue and alcian blue for proteoglycan production. The stained images were taken using a light microscope (Leica Microsystems, Germany).

Different joint tissue constructs for joint reconstruction were fabricated using 3D bioprinting with OPUS (Novaprint). 3D bioprinting cell-laden hydrogels together with biodegradable polymers was conducted for specific articular joint. The motion program and alignment of cell-laden hydrogel and PCL fibers were demonstrated in the printing process of anisotropic cartilage tissues in movie S1. Bioprinting rabbit-derived MSC-laden hydrogels together with physically and chemically gradient biodegradable polymers was conducted for knee cartilage repair using OPUS. The rMSCs suspension (a total of 1 107 cells) was loaded into the composite hydrogel (table S1). The printing chamber was kept at a constant 17C. The native cartilage structure inspired us to produce four-layer 3D structures by placing together cell-laden hydrogel and PCL (~100-m diameter for hydrogel and ~200-m diameter for PCL) to construct a composite cartilage scaffold (17). Needle sizes for the hydrogel and PCL were 100 and 200 m, respectively. Briefly, PCL was molten (~60C) to fabricate the physically gradient supporting structure for the scaffold, while MSC-laden hydrogel (~37C) encapsulating PLGA microparticles carrying TGF3 or BMP4 in different layers was bioprinted into the microchannels between PCL fibers from different syringes (movie S1). During plotting, the needle diameter, layer thickness, and speed for PCL printing were kept constant at 200 m, 200 m, and 180 mm/min, respectively, as previously reported (15). The extrusion pressure for PCL and hydrogel was 1.2 to 1.8 kPa and 0.5 to 0.8 kPa, respectively. The fiber spacing was kept constant at 150 or 750 m for NG scaffolds and varied gradually from 150 to 750 m throughout the gradient scaffolds. The gradient microchannels between PCL range gradually from 150 m wide from the superficial zone of the cartilage to 750 m wide in the deep zone of the cartilage construct. The fiber spacing was changed every millimeter. The scaffolds were plotted in blocks of 4 4 4 mm for rabbit cartilage construct and 14 14 14 mm for human cartilage construct.

rhTGF3 and rhBMP4 were microencapsulated in PLGA (50:50 PLA/PGA) S to deliver TGF3 (20 ng/ml) and BMP4 (100 ng/ml) in hydrogel as previously described (15, 17). TGF3 and BMP4 S were mixed in the cell-laden hydrogel (table S1), respectively, and printed into the microchannels between PCL fibers with different syringes. To chemically simulate the deep layer in native cartilage, PLGABMP4-encapsulated MSC-laden hydrogel was used in the deepest layer with a 750-m PCL fiber spacing, while PLGATGF3 was used for the other three layers of the cartilage construct. Generated PLGA S was shown with SEM. Printability was also shown with a test run for the PLGA-encapsulated MSC-laden hydrogel. Release kinetics of TGF3 and BMP4 from PLGA S were measured by incubating S (10 mg/ml) encapsulating TGF3 (0.1% bovine serum albumin) or BMP4 [in phosphate-buffered saline (PBS)] at 37C with mild agitation for up to 60 days. Upon centrifugation at 2500 revolutions per minute for 5 min, supernatant of the PLGA S incubation solution was collected. Released TGF3 and BMP4 concentration was measured using enzyme-linked immunosorbent assay kits following the manufacturers protocols (15). To validate S distribution in MSC-laden hydrogel, fluorophore-conjugated rhodamine was encapsulated into PLGA S and delivered to the hydrogel. At day 7, PLGA rhodamine S and cell viability (live/dead assay) in the hydrogel was observed under a confocal microscope.

To validate the cartilage-generating capability of the composite scaffold, the protein-carrying scaffolds were incubated and observed for 12 weeks in vitro. Photographs of cartilage-like tissue development surrounding the scaffolds were taken to show the cartilage-generating potential in vitro of the scaffolds. Mechanical measurements on scaffolds and native cartilage were carried out with a single-column static instrument (Instron 5843, USA) equipped with two flat compression stages and a 10-N load cell.

To see the differences within the rMSCs cultured in the different areas of the gradient scaffolds, after 6 weeks under differentiation conditions, the constructs were collected, washed three times with PBS, and cut in four portions of 1 mm in height. The images of each layer were taken using a light microscope. The viability of the BMSCs on the scaffolds were analyzed with live/dead assay and observed under confocal microscopy for 3, 7, and 21 days, while the morphology of cells was observed under confocal microscopy at end point (21 days). Briefly, The MSCs in the scaffold were fixed with 4% paraformaldehyde and treated with rhodamine phalloidin (Thermo Fisher Scientific, USA) to stain the F-actin for 1 hour and incubated with DAPI (Thermo Fisher Scientific, USA) to stain the nucleus for 5 min in turn. Cell proliferation in the constructs was assessed with alamarBlue assay kit (DAL1100; Life Technologies) according to the manufacturers instruction as previously described (12).

Biochemical studies were performed to the full and partitioned scaffolds. Toluidine blue and alcian blue staining were applied to determine the production of GAGs in each layer of the gradient scaffold. The sections for the different layers were prepared and then treated with Safranin O and toluidine blue staining to identify GAG formation in each layer. Immunofluorescence staining of chondrocyte markers (PRG4, Col2A1, aggrecan, and Col10A1) was conducted for layer-specific chondrogenesis and observed under confocal microscopy.

Different groups of scaffolds were transplanted under the dorsal skin of nude mice in vivo subcutaneously for 12 weeks. The cartilage scaffolds were retrieved after 12 weeks in vivo, and zone-specific expressions of PRG4, aggrecan, and type II and X collagens were assayed with immunofluorescence. GAG production was determined with toluidine blue and alcian blue staining.

Adult male New Zealand white rabbits weighing 3.0 to 3.5 kg were used for the study in vivo. Rabbits were randomized into three groups (two knees of each rabbit were used): NG-750 (BCS group), NG-150 scaffold (BMS group), and the gradient scaffold (DS group). After anesthesia, the knee joint of the rabbits was exposed after dislocating the patella. A cylindrical defect (4-mm diameter, 4-mm depth) on the trochlear groove of the distal femur was created using corneal trephine. Then, suited 3D bioprinted BCS, BMS, or DS scaffolds were implanted matching with the defect. Forced flexion and extension were conducted for the operated knee to confirm the localization of the implanted scaffolds in the defect. Last, the operated knee joint was closed with suture (4-0 thread), and antibiotics were given intramuscularly for prophylactic infection. After the operation, rabbits were allowed to move freely in their single cages and fed with standard food and water. Eight, 12, and 24 weeks later, rabbits were euthanized for further study. The protocol was approved by the local Institutional Animal Care and Use Committee and complied with the Guide for the Care and Use of Laboratory Animals, revised in 2010 and published by the National Academy of Sciences.

Serial sections (4 mm thick) were cut sagittally through the center of the operative site and stained with H&E, toluidine blue, Safranin O and fast green, toluidine blue, alcian blue, and picrosirius red according to standard protocols. Immunohistochemical staining of markers (PRG4, RUNX2, and collagens II and X) for chondrocyte phenotype and microvessel ingrowth (CD31 and smooth muscle actin) was conducted according to standard protocols in the generated cartilage tissue sections in different groups compared with the native cartilage. The stained images were taken, and regenerated cartilage thickness (n = 6 for each) was calculated for different bioprinted scaffolds using a light microscope. A modified method was used to evaluate the histological repair of articular cartilage defects (18).

Acknowledgments: Funding: This work was funded by the National Key R&D Program of China (nos. 2018YFB1105600 and 2018YFA0703000), the China National Natural Science Funds (nos. 51631009 and 81802122), the Chinese postdoctoral funding (no. 2019M661559), and the Funds from Shanghai Jiao Tong University for the Clinical and Translational Research Center for 3D Printing Technology. Author contributions: Y.S. and Y.Y. contributed equally to conceiving the study and designing the experiments. W.J. helped design the 3D bioprinted scaffolds. B.W. helped synthesize the growth factorencapsulated microspheres. Y.S. and Q.W. conducted the animal experiment. Y.S. and Y.Y. analyzed the data and wrote the manuscript. K.D. helped edit the manuscript and provided oversight. All authors read and approved the final manuscript. Competing interests: The authors declare that they have no competing interests. Data materials and availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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3D bioprinting dual-factor releasing and gradient-structured constructs ready to implant for anisotropic cartilage regeneration - Science Advances

Bone Marrow Stem Cells Comments Off on 3D bioprinting dual-factor releasing and gradient-structured constructs ready to implant for anisotropic cartilage regeneration – Science Advances | September 9th, 2020

A graduate has revealed how her ultimate adventure became a nightmare when she was told her jetlag" was in fact leukemia so aggressive it had invaded 90 percent of her blood, when she was 5,000 miles from home.

After gaining a Fine Art degree at Newcastle University, Ella Dawson jetted to Colombia for a seven-week backpacking trip.

Putting the exhaustion, nausea and dizziness she experienced shortly after arriving down to jetlag, it was only when mysterious bruises sprang up all over her body, that Dawson saw a doctor in the city of Santa Marta.

Ella during CAR-T treatment (PA Real Life/Collect)

Now receiving a complex and innovative treatment called CAR-T, which removes and reprograms" her blood cells to fight cancer, the medic sent her for a series of blood tests resulting in her leukemia diagnosis in August 2019.

By the time I got my diagnosis, I was so unwell that I was expecting a bombshell," she said.

But it was such a chaotic situation that I almost didn't have any time to process everything. I was thousands of miles away from home, having to use my phone to translate, while doctors explained what was going to happen."

Ella recovering back home (PA Real Life/Collect)

Even now, I still struggle with the idea that I have cancer. It almost feels like there's a stigma around it, especially when you're young and, on all of the leaflets I was given, everybody looked so unwell and depressed," she continued.

It's not been easy, but I've been determined to make the most of the good times and strive for moments of normality when I can. It's what's got me through."

Looking back, Dawson believes her cancer symptoms first began to show in around April 2019, when she returned home for the Easter holidays and felt run down and fatigued.

Ella at an art exhibition she held as part of her university course (PA Real Life/Collect)

I was usually quite fit and would go to the gym four times a week, but I found myself struggling to keep up," she said.

Busy studying, she put her symptoms down to final year stress.

Dawson has had an under-active thyroid, which can also cause tiredness, muscle aches and weakness, according to the NHS.

Ella recovering back home (PA Real Life/Collect)

I thought my tiredness was just a combination of the two," she said.

Once her degree show was over in June and she moved back to Huddersfield, she was soon distracted by thoughts of the seven-week trip around Colombia.

In the weeks leading up to her departure in August, she became increasingly worn down and kept catching bugs and colds. On one particularly memorable occasion, feeling so dizzy after just 30 minutes of horseback riding that she almost passed out.

I saw the doctor to be on the safe side and she took my blood pressure," she said.

Everything looked normal, so I was told it was likely just the heat making me feel faint. The doctor said to come back a week later if I felt worse, but I'd be in Colombia by then, so I couldn't."

The day I left for my trip, I looked and felt absolutely knackered, but I just kept telling myself that once I got there and relaxed, I'd be fine."

Ella in Colombia (PA Real Life/Collect)

Touching down in Bogota, Dawson felt so exhausted that she spent the first three days of her trip in bed.

I could barely walk, let alone get out to explore. I spoke to the staff at the hostel where I was staying at and they reassured me that, because Bogota has a high altitude, a lot of people struggle to acclimatize when they first arrive," she said.

That, plus the jetlag, made perfect sense, so I didn't worry too much."

Ella in Colombia (PA Real Life/Collect)

After around a week, Dawson began to rally and was able to make her way around the country as planned.

But things changed drastically during a six-hour trek through the jungle.

Usually I'd be bounding ahead, but I was having to stop and sit down every five minutes. My body couldn't cope. It was too late to turn back, so I had to keep going. By the end, I felt so dizzy and nauseous," she said.

Ella on the six-hour hike in Colombia (PA Real Life/Collect)

Over the following week, Dawson's condition dramatically declined.

I couldn't even walk to the shop or stand up for long enough to make myself dinner. I was in pain all the time," she said.

My bones were aching and I was covered in so many bruises that I looked like I'd been hit by a bus."

Ella on the six-hour hike in Colombia (PA Real Life/Collect)

Worried, Dawson decided to visit a doctor, who told her that she probably had a low platelet count and ran some blood tests, sending the results back to her GP in the UK for a second opinion, which took four days to obtain.

By that point, she felt so unwell she had decided to go home and was on the verge of booking a flight when she received a phone call from the Colombian doctor, urging her not to travel.

I had no idea what was going on. I was told, 'don't get on a plane come straight to hospital,'" she said. The hostel manager was fantastic and sorted out a car to take me there and helped me ensure all my insurance was in order."

Today is #WorldLeukemiaDay Help raise awareness of leukaemia and its symptoms. Find out more here https://t.co/Di8yYWNV7C

Dawson was admitted to intensive care, where further tests were run before she was transferred to a larger, more specialist hospital the following day.

There, she was told that she had leukemia, a form of cancer affecting the bone marrow and blood cells.

Medics also explained that her blood platelet levels were dangerously low, making flying home too risky.

The bruise-like spots on Ella's legs (PA Real Life/Collect)

They said if they couldn't get my platelet count up and soon I'd have to start chemotherapy in Colombia," she added.

By that point, Dawson's mom Jane and dad Kevin had been told her diagnosis by her doctor in the UK and were flying over to be by her side.

They arrived about a day-and-a-half after I'd been given the news," she said. It made me realize how much I'd missed them."

Ella in hospital (PA Real Life/Collect)

Over the next week, Ella had seven blood transfusions and five bags of donor platelets pumped through her body.

Thankfully, the treatment stabilized her enough to fly home.

There had been talk of using a medical plane, but we didn't need one in the end," she said. I was put in first class, so I could lie down, but I was so exhausted that I slept the whole way."

Ella leaving hospital (PA Real Life/Collect)

Once back in the UK, Dawson went to Huddersfield Royal Infirmary for a biopsy before being transferred to St James' University Hospital in Leeds, where it was confirmed she had acute lymphoblastic leukemia (ALL), which is characterized by an overproduction of immature white blood cells.

According to the charity Leukemia Care, who have been tirelessly supporting Ella throughout her journey, ALL accounts for less than one percent of cancer cases in the UK.

I wasn't given a stage, but I later found out that, at the time of my diagnosis, 90 percent of my blood had been invaded by cancer cells," she added.

Ella after losing her hair (PA Real Life/Collect)

In September 2019, Dawson began chemotherapy, which left her immune system so compromised that she had to stay in hospital in isolation.

When I started chemo, I was given a six-month treatment plan, which helped me to get my head around things," she said.

But around a month in, after the first round, it was clear it wasn't working, so doctors said they needed to change to a different type."

That was very difficult the chopping and changing. As doctors wanted to respond to what was happening immediately in front of them, we could only plan a month or so ahead, which made it hard to wrap my mind around."

In November, Dawson started her adapted treatment regime, which involved having four different types of chemotherapy every day for five days.

That was one of the worst times so far. My whole body was in excruciating pain. I'd get splitting headaches, blurred vision and lost all my hair," she said.

Ella in hospital for the second round of her treatment (PA Real Life/Collect)

In December, she was discharged being told shortly afterwards that she was in morphological remission, which happens when the number of blast cells found in the bone marrow is less than five percent.

Next, she was due to have a stem cell transplant, the preparation for which involved having two rounds of a treatment that meant immunotherapy drugs were constantly infused into her body through a portable pump.

I had to take it everywhere with me. I even went clubbing with it a few times," she said.

Ella with her immunotherapy drug bag (PA Real Life/Collect)

Two days before her stem cell transplant date in 2020, pre-operative tests showed that Dawson had relapsed.

I didn't believe them at first as I felt absolutely fine," she said.

Doctors then decided to refer me for CAR-T treatment, but as it involved harvesting my blood cells and sending them away to be reprogrammed to fight the cancer, the [virus] created some delays in getting them back."

While I waited, doctors struggled to keep the cancer at bay. It was developing really fast."

Ella's radiotherapy head mask (PA Real Life/Collect)

Tests found cancer cells in my spinal fluid, so I had to have two lumbar punctures a week to drain it, which was awful, but it did clear it. I also had five days' worth of radiotherapy on my right eye as a precaution after it became inflamed," she said.

Finally, in June, Dawson began CAR-T treatment at Manchester's Christie Hospital and is now awaiting tests to see how successful it has been with her consultants remaining hopeful that it has eradicated all traces of cancer from her body.

Currently recovering at home with her family, Dawson is keen to shine a light on Leukemia Care's "Spot Leukemia" campaign to raise awareness of the six most common signs of the disease.

Ella getting her cells harvested for CAR-T treatment (PA Real Life/Collect)

I am the perfect example of somebody who never believed this would happen to me," she said.

It's important to listen to your body and learn when to push yourself and when to rest."

I also want anybody reading this who might be going through what I did to know that, while it sometimes feels impossible to stay positive, by keeping moving and finding the bright side where you can, you can get through."

Ella now (PA Real Life/Collect)

Staying positive has very much been aided by the excellent care I've received from the teams at St. James Hospital in Leeds and The Christie in Manchester, so I want to thank them, too," she continued.

Dawson is working closely with the charity Leukemia Care's 'Spot Leukemia' campaign to raise awareness of leukemia. Find out more at http://www.spotleukaemia.org.uk

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Graduate Devastated After Learning 5,000 Miles From Home That Her 'Jetlag' Is Aggressive Leukemia - Comic Sands

Bone Marrow Stem Cells Comments Off on Graduate Devastated After Learning 5,000 Miles From Home That Her ‘Jetlag’ Is Aggressive Leukemia – Comic Sands | September 8th, 2020

PHOENIX, Sept. 8, 2020 /PRNewswire/ --(OTC CELZ) -- Creative Medical Technology Holdings Inc. announced today receipt of a Notice of Allowance from the United States Patent and Trademark Office for its patent application, "Perispinal Perfusion by Administration of T Regulatory Cells Alone or in Combination with Angiogenic Cell Therapies."

The patent covers the use of activated T regulatory cells for inducing an increase in blood circulation in areas surrounding the disc of patients with lower back pain. It is believed that a significant proportion of patients suffering from lower back pain have abnormally poor circulation, which does not effectively remove waste products and irritants. Restoration of circulation in the lower back is associated with reduction of pain.

The Company acquired a previously granted US Patent # 9,598,673 covering use of various types of stem cells, autologous and allogeneic, for treating lower back pain. The Company has completed an autologous cell therapy pilot study in the area of lower back pain utilizing this patented technology and is currently in the process of assembling data for publication.

"Creative Medical Technology Holdings is developing a critical mass of issued intellectual property covering multiple cell therapy treatments of lower back pain as well as other indications," said Timothy Warbington, President and CEO of the Company. "Testimony to the size of the lower back pain market is the $1 Billion Mesoblast-Grunenthal deal for a pre-review cell therapy product1. We are enthusiastic to add this new therapy to our expanding portfolio of rapid-to-commercialize cellular therapies."

Creative Medical Technology Holdings has previously commercialized its CaverStemR technology involving personalized bone marrow cellular therapy for erectile dysfunction. This technology is covered by issued patent # 8,372,797 and a clinical trial demonstrating safety with signals of efficacy published in the peer-reviewed literature2.

"Immunotherapy is one segment of the biotechnology industry that is expanding at an exponential rate," said Donald Dickerson, CFO of the Company. "The recent Nobel Prize in the area of Immunotherapy of Cancer, as well as the current valuations of immunotherapy companies, validates the approaches that we have been developing, and now patenting. Essentially our approach is to use stem cells, or immunotherapy to enable the body to heal itself."

"The Company welcomes the biotechnology/life sciences community and key opinion leaders to contact us to discuss potential collaboration on our patented technologies in this amazing space," Mr. Warbington said further.

About Creative Medical Technology Holdings

Creative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in stem cell technology in the fields of urology, neurology and orthopedics and trades on the OTC under the ticker symbol CELZ. For further information about the company, please visit http://www.creativemedicaltechnology.com.

Forward Looking Statements

OTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website at http://www.sec.gov.

Creativemedicaltechnology.comwww.StemSpine.com http://www.Caverstem.com http://www.Femcelz.com

1 https://www.biopharma-reporter.com/Article/2019/09/12/Gruenenthal-partners-with-Mesoblast-for-back-pain-cell-therapy#:~:text=Gr%C3%BCnenthal%20agrees%20deal%20with%20Mesoblast,disease%20in%20previously%20treated%20patients.

2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958721/

SOURCE Creative Medical Technology Holdings, Inc.

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Application of Immunotherapy to $7 Billion Lower Back Pain Market Patented by Creative Medical Technology Holdings - PRNewswire

Bone Marrow Stem Cells Comments Off on Application of Immunotherapy to $7 Billion Lower Back Pain Market Patented by Creative Medical Technology Holdings – PRNewswire | September 8th, 2020

A novel Bcl-2 inhibitor, APG-2575, has been granted an Orphan Drug designation (ODD) by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL), announced Ascentage Pharma in a press release.1

This marks the second ODD for APG-2575, after 1 was granted to the drug in July 2020 for the treatment of Waldenstrm Macroglobulinemia (WM).2

At present, CLL still presents considerable unmet medical needs. APG-2575 is a key drug candidate in Ascentage Pharma's pipeline targeting apoptosis. The APG-2575 received this ODD from the FDA shortly after the first ODD in WM, and this designation will be helpful in enhancing our communication with the FDA and expediting our development of APG-2575 in these rare cancer diseases," said Yifan Zhai, MD, PhD, chief medical officer, Ascentage Pharma, in a statement.1 All the policy support and incentives as a result of this ODD will help us accelerate the global clinical development of APG-2575, which we hope will soon offer additional treatment options for patients with CLL."

In hematologic malignancies, APG-2575 may selectively block Bcl-2 as a way to renew the apoptosis process in cancer cells. The first study of APG-2575 in CLL, as well as in small lymphocytic leukemia (SLL), is currently recruiting 35 patients with relapsed or refractory disease. In the phase 1b dose-escalation study (NCT04215809), patients will receive APG-2575 alone or in combination with other therapeutic agents. The primary end point of the study is dose-limiting toxicity, and the secondary end point is the maximum tolerated dose of APG-2575.

The study will follow a non-randomized 3 + 3 design at a starting dose of 200 mg given on day 1 of a 28-day cycle. The dose will be increased to 400 mg, followed by 600 mg, 800 mg, and 1200 mg.

To be included in the trial, patients must be 18 years or older with a histologically confirmed diagnosis of CLL/SLL, and ECOG performance status of 2 or lower, adequate bone marrow function, and a serum creatinine level of 1.5upper limit of normal. In part 1, patients will be eligible for dose escalation if they have received 3 or fewer prior lines of systemic therapy. Female patients are required to be postmenopausal for 2 years or surgically sterile prior to beginning treatment in the study.

Patients are excluded from this study if they have undergone allogeneic stem cell transplant within 90 days of joining the study, have active graft-versus-host-disease or are in need of immunosuppressive therapy, and/or have Richter's syndrome. The study also excludes patients with certain prior therapies and comorbidities that may interfere with APG-2575 treatment.

Multiple cancer centers in the United States are involved in the phase 1b study of APG-2575 including the Mayo Clinic in Scottsdale Arizona, City of Hope in Duarte, California, Dana-Farber Cancer Institute in Boston, Massachusetts, Novant Health in Charlotte, North Carolina, Grabrail Cancer Center in Canton, Ohio, Cleveland Clinic in Cleveland, Ohio, and Swedish Health in Seattle, Washington.

Outside of the realm CLL/SLL, APG-2575 is being investigated in other hematologic malignancies like WM, AML, and T-cell prolymphocytic leukemia. Studies of APG-2575 in these disease states are currently recruiting patients in centers in the United States, Australia, and China.

References:

1. Ascentage Pharma's Bcl-2 inhibitor apg-2575 granted Orphan Drug designation by the FDA for the treatment of chronic lymphocytic leukemia. News release. Ascentage Pharmaceuticals. September 7, 2020. Accessed September 8, 2020. https://prn.to/2ZiOqFJ

2. Ascentage Pharmas Bcl-2 inhibitor apg-2575 granted Orphan Drug Designation by the FDA for the treatment of waldenstrm macroglobulinemia. News release. Ascentage Pharmaceuticals. July 15, 2020. Accessed September 8, 2020. https://bit.ly/329A5gL

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FDA Grants Orphan Drug Designation to Novel Bcl-2 inhibitor in CLL - Targeted Oncology

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Hematopoietic stem cells are young or immature blood cells found to be living in bone marrow. These blood cells on mature in bone marrow and only a small number of these cells get to enter blood stream. These cells that enter blood stream are called as peripheral blood stems cells. Hematopoietic stem cells transplantation is replacement of absent, diseased or damaged hematopoietic stem cells due to chemotherapy or radiation, with healthy hematopoietic stem cells. Over last 30 years hematopoietic stem cells transplantation market seen rapid expansion and constant expansion with lifesaving technological advances. Hematopoietic stem cells transplantation is also known blood and marrow transplantation which brings about reestablishment of the patients immune and medullary function while treating varied range of about 70 hematological and non-hematological disorders. In general hematopoietic stem cells transplantation is used in treatment of hereditary, oncological, immunological and malignant and non-malignant hematological diseases.

There are two types of peripheral blood stem cell transplants mainly autologous and allogeneic transplantation. In autologous transplants patients own hematopoietic stem cells are harvested or removed before the high-dose treatment that might destroy the patients hematopoietic stem cells. While in allogeneic transplants stem cells are obtained from a tissue type of matched or mismatched donor. Hematopoietic stem cells are harvested from blood or bone marrow and is then frozen to use later. Depending upon the source of hematopoietic stem cells, worldwide there are three types of hematopoietic stem cells transplants namely bone marrow transplant (BMT), peripheral blood stem cell transplant and cord blood transplant. Major drivers in the hematopoietic stem cells transplantation market are establishment of strong and well developed network of hematopoietic stem cells transplantation organizations having global reach and presence has recognized NGO named Worldwide Network for Blood and Marrow Transplantation Group (WBMT) in official relation with World Health Organization (WHO) and rapid increase in number of transplants. Major restraints in hematopoietic stem cells transplantation market is high cost of transplantation and lack of funding for WBMT and other organizations such as regional, national and donor.

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The global market for Hematopoietic stem cells transplantation market is segmented on basis of transplant type, application, disease indication, end user and geography:

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Based on transplantation type, hematopoietic stem cells transplantation market is segmented into allogeneic and autologous. Hematopoietic stem cells transplantation market is also segmented by application type into bone marrow transplant (BMT), peripheral blood stem cell transplant and cord blood transplant. The market for hematopoietic stem cells transplantation is majorly driven by bone marrow transplant (BMT) segment. Based on end user hematopoietic stem cells transplantation market is segmented into hospitals and specialty centers. Peripheral blood stem cell transplant type holds the largest market for hematopoietic stem cells transplantation. Hematopoietic stem cells transplantation market is further segmented by disease indication into three main categories i.e. lymphoproliferative disorders, leukemia, and non-malignant disorders. Segment lymphoproliferative disorder holds largest share amongst the three in Hematopoietic stem cells transplantation market. On the basis of regional presence, global hematopoietic stem cells transplantation market is segmented into five key regions viz. North America, Latin America, Europe, Asia Pacific, and Middle East & Africa. Europe leads the global hematopoietic stem cells transplantation market followed by U.S. due to easy technological applications, funding and high income populations. Other reasons for rise in hematopoietic stem cells transplantation market is high prevalence of lymphoproliferative disorders and leukemia; demand for better treatment options; and easy accessibility and acceptance of population to new technological advances. Transplantation rates in high income countries are increasing at a greater extent but continued rise is also seen in low income countries and expected to rise more. Hematopoietic stem cells transplantation market will have its potential in near future as being a perfect alternative to traditional system in many congenital and acquired hematopoietic disorders management. While India, China and Japan will be emerging as potential markets. An excellent and long term alternative to relief by side effects of chemotherapy, radiotherapy and immune-sensitive malignancies is another driver for hematopoietic stem cells transplantation market. The key players in global hematopoietic stem cells transplantation market are Lonza, Escape Therapeutics, Cesca Therapeutics Inc., Regen BioPharma, Inc., Invitrx Inc, StemGenex, Lion Biotechnologies, Inc., CellGenix GmbH, Actinium Pharmaceuticals, Inc., Pluristem, Kite Pharma, Novartis AG.You Can Request for TOC Here @ https://www.persistencemarketresearch.com/toc/14563

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Global Hematopoietic Stem Cells Transplantation Market to Witness Rapid Development During the Period 2017 2025 - The News Brok

Bone Marrow Stem Cells Comments Off on Global Hematopoietic Stem Cells Transplantation Market to Witness Rapid Development During the Period 2017 2025 – The News Brok | September 7th, 2020

The NIH is pitching $14.6 million into a three for one HIV research program led by USC and the Fred Hutchinson Cancer Research Center that aims to strike the need for daily medication or even achieve a home run cure.

The five-year grant will back preclinical studies that combine gene editing with technology to improve bone marrow transplants. The potential therapy would engineer a patients own stem cells to fight HIV, and stimulate them to produce new immune cells once reintroduced to the patient.

A home run would be that we completely cure people of HIV, Paula Cannon, a USC professor of molecular microbiology and immunology and co-director of the program, said in a statement. What Id be fine with is the idea that somebody no longer needs to take anti-HIV drugs every day because their immune system is keeping the virus under control, so that it no longer causes health problems and, importantly, they cant transmit it to anybody else.

Hans-Peter Kiem, the Stephanus Family Endowed Chair for Cell and Gene Therapy at Fred Hutch, is the co-director. Harvard University professor David Scadden and Magenta Therapeutics are also collaborating on the project.

The approach was inspired by three patients who appear to have been cured of the virus all of whom received blood stem cell transplants from donors who carried a mutation in the CCR5 gene. One of them, dubbed the Berlin patient, has been off antiretroviral drugs since 2007.

I think of the Berlin patient as proof of principle that replacing the immune system with one thats HIV-resistant by removing CCR5 is a possible way to treat somebody, Cannon said.

The program will study the use of gene editing to remove CCR5 from patients stem cells a process which is already in clinical trial for HIV treatment at City of Hope National Medical Center in Duarte, CA. The stem cells will also be engineered to release antibodies and antibody-like molecules that block HIV.

In addition, the grant will fund a Fred Hutch teams endeavor to adapt CAR-T cell therapy to create stem cells whose progeny target HIV-infected cells.

As for preparing a patient for the transplant,Magenta is working on antibody-drug conjugates to replace mild chemotherapy or radiotherapy typically given before the procedure. And Scadden is researching an injectable gel that could help immune cells repopulate more quickly, avoiding a delay.

HIV infection, which currently affects about 1.2 million Americans, has proved to be exceedingly difficult to cure. In July, Merck and Dewpoint inked a deal that allows the pharma to use the Boston-based biotechs biomolecular condensate technology to develop treatments, and potentially a cure, for the HIV virus. The NIH-funded group is hoping to at least control the virus enough to eliminate the need for daily meds. But at best, theyre also eyeing a long sought-after cure.

This grant funds a team with an overarching goal of developing what our perfect HIV gene therapy would look like, Cannon said. All of these pieces could happen separately, but the fact that the NIH has funded us as a team means that the sum will be so much bigger than the parts.

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Researchers teamed up to develop a 'three in one' HIV treatment and the NIH is throwing in $14.6M - Endpoints News

Bone Marrow Stem Cells Comments Off on Researchers teamed up to develop a ‘three in one’ HIV treatment and the NIH is throwing in $14.6M – Endpoints News | September 5th, 2020

In 2016, Danny Wade, a successful marketing professional and an active and doting father to his three young children, aged 11, 8 and 6, checked himself into the emergency department when he began experiencing severe, inexplicable bone pain and unusual fatigue.

Two days later, after undergoing a battery of tests, Danny was diagnosed with multiple myeloma, a little-known and incurable cancer of the plasma cells. He was just 42 years old.

"I was shocked when I got the news, Danny recalls. What upset me most was when the doctor told me that the average life expectancy for myeloma patients was only five to seven years. The thought that I would not see my children grow up was devastating. I knew I had to fight for my life.

Thats exactly what Danny has been doing. Within six months of being diagnosed, Danny went through a difficult high-dose chemotherapy regimen to prepare for an autologous stem cell transplant using his own stem cells. Then in 2017 after further tests, Dannys doctors recommended that his best option for survival was to undergo another transplant with stem cells from a healthy donor. He took his doctors advice and underwent the procedure. Fortunately, he was eligible to participate in a clinical trial at Maisonneuve-Rosemont Hospital where he received a breakthrough therapy involving bi-weekly injections that he will continue to take for a year.

Dannys condition is relatively stable at this time, and he extremely thankful to still be alive. He is thrilled to watch his children grow and to resume being an active part of their lives. He credits his survival to the life-saving treatments that he has access to and the love and support he receives from his partner, Anik. With my beloved Anik by my side, Ive had the courage to get through this nightmare and to have faith that I can get through whatever else the future holds.

Danny is eager to do what he can to help others living with myeloma. I made a promise that once I was doing well, I would do everything in my power to help find a cure so that other patients dont have to live through the horrors I have," says Danny. Danny is a member of the organizing committee of the Montreal Support Group, and recently co-founded the South Shore Myeloma Support Group.

Over the past four years, Danny has seen, first-hand, the life-changing impact that advances in myeloma research are having on the lives of those living with this incurable cancer. Thats why he and his family are more intent than ever to raise as much awareness and funds for myeloma as they can, and will be participating in Myeloma Canadas 12th annual Montreal Multiple Myeloma March on Sunday, September 20, at 10 am.

This years Montreal March has been modified to help stop the spread of COVID-19. In compliance with physical distancing measures, participants are encouraged to hold their own walk in their neighbourhood at the same time as the regularly scheduled March on September 20. Danny and his fellow Montreal Marchers have set their fundraising goal at $60,000 to help further crucial research for this deadly blood cancer that affects nine new Canadians every day.

Myeloma research has produced extremely promising results over the past two decades. In fact, for the first time, theres a cure in sight, says Dr Richard LeBlanc, Medical Hematologist and Oncologist, and holder of the Myeloma Canada Chair in Multiple Myeloma Research at the Universit de Montral. We cant afford to let the current situation stop the progress weve made and put vulnerable people living with myeloma at risk, which is why its more crucial than ever to invest in research and find a cure.

The Multiple Myeloma March, Myeloma Canadas flagship fundraiser is now in its 12th year. The annual five-kilometer event brings Canadian communities together to raise essential funds for research and to help improve the lives of all Canadians impacted by myeloma. Montreal is one of a record 33 communities across the country to be included in this years Multiple Myeloma March. The national fundraising goal is set at $650,000. To learn more about how this event will be working, please click here.

While this years March will undoubtedly be different because of the pandemic, its crucial to stay positive, says Martine Elias, Executive Director of Myeloma Canada. Fundraising has taken a huge hit for many organizations. We need to do all we can to increase awareness and raise essential funds for research that will improve the lives of Canadians impacted by myeloma, and bring us closer to a cure, Martine added. As we mark Myeloma Canadas 15th anniversary, we celebrate the strength of our incredible community. More than ever, were counting on our supporters to help us achieve our goal of $650,000. Canadians impacted by this incurable cancer are depending on us.

This year, a minimum of 50% of funds raised by the Multiple Myeloma March will go directly to support Myeloma Canadas Myeloma Research Priority Setting Partnership (PSP), the first program of its kind in myeloma. The PSP will use input provided by the Canadian myeloma community to identify and define investments in myeloma research over the next 18 months. The balance raised will go toward supporting various myeloma research projects and initiatives that are pivotal for improving quality of life and moving the needle toward a cure.

Multiple myeloma, also known as myeloma, is the second most common form of blood cancer. Myeloma affects a type of immune cell called the plasma cell, found in the bone marrow. Every day, nine Canadians are diagnosed, yet in spite of its growing prevalence, the disease remains relatively unknown. While there is no cure, people with myeloma are living longer and better lives, thanks to recent breakthroughs in treatment. To find the cure, more funding and research are required. To learn more, or to donate, please visit http://www.myeloma.ca

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Father of Three with Incurable Cancer is Helping Researchers Get One Step Closer to a Cure - The Suburban Newspaper

Bone Marrow Stem Cells Comments Off on Father of Three with Incurable Cancer is Helping Researchers Get One Step Closer to a Cure – The Suburban Newspaper | September 5th, 2020

WASHINGTON, Sept. 4, 2020 /PRNewswire/ -- During the COVID-19 pandemic, many stem cell transplant centers including guidance from the National Marrow Donor Program (NMDP) recommend that stem cell products be frozen for preservation. However, a new study in Blood Advances suggests that the freezing process can decrease the quality of stem cells, particularly if they were manipulated before being preserved, if they had high white blood cell content, or if they were stored for a long period of time.

Stem cells can develop into many different types of cells, so they are often used in treatment to replace or repair damaged organs or tissues. Allogeneic stem cell transplantation, which involves transferring stem cells from a healthy donor to a patient, can treat a variety of diseases, including leukemia, lymphoma, myeloma, thalassemia, and sickle cell disease.

Before the coronavirus outbreak, it was not common to freeze allogeneic donor stem cells prior to infusion. However, due to COVID-19's effects on donor and hospital availability, as well as new travel and transportation restrictions, more transplant centers including the NMDP are recommending cryopreservation.

"Prior to COVID-19, the donor and transplant systems were well coordinated and effective. Now, with irregular flights and closed borders, travel and transportation are not assured," said lead study author Duncan Purtill, MD, of Fiona Stanley Hospital in Western Australia. "Five to seven days before stem cell transplant, the recipient usually starts chemotherapy to remove all their bone marrow cells. Without a healthy transplant to replace the cells on the same day, they would be left with no functioning bone marrow, which would of course be very high risk and carry a poor prognosis. Life literally depends on the safe arrival and immediate infusion of stem cells."

Dr. Purtill and his team analyzed 305 samples of allogeneic stem cell products that were cryopreserved at participating Australian cell processing labs between 2015 and 2019. They found that, on average, the recovery of the stem cell products was 74%. This is considered an acceptable, viable recovery, enabling the cells to be used in transplantation. However, some products did not recover to that level: around 15% of the surveyed products had a cell recovery of less than 50%. In fact, the study found that quality recovery could range as low as just 6%. Such a significant cell loss after thawing may mean that the remaining cells may be too few, or too damaged, to achieve timely bone marrow recovery in the patient after infusion.

"It seems that there is variability in recovery and more work needs to be done to determine why," said Dr. Purtill. "When we freeze stem cells and then thaw them afterwards, we sometimes get unexpected results. In this study we identified some possible factors influencing that variability."

The research team pointed to three possible reasons for the loss of quality in some of the stem cells products they analyzed. First, they noted that prolonged transportation and storage time prior to cryopreservation was associated with a loss of quality. They also found that higher white cell concentration of the product affected its quality. It was thought that the presence of other white cells could adversely affect the stem cells, either by releasing damaging enzymes or chemicals, or else by consuming nutritional elements within the product and resulting in less healthy stem cells. And finally, they pointed out that a small proportion of cells which underwent complex manipulation before being frozen also suffered quality loss for instance, when the cell processing lab removed lymphocytes or washed the product to remove plasma and other noncellular components.

Dr. Purtill and his collaborators expressed hope that their findings could serve to inform and improve stem cell transplantation, collection, and processing procedures. "Our findings could be a note of caution for transplant centers to not take for granted that the frozen product they have received will show perfect recovery once thawed," said Dr. Purtill. "I hope centers will insist on receiving a pilot vial which has been frozen and transported in the same way. They can assess the pilot vial to determine its viability before they use the full product and start chemotherapy for the patient."

Blood Advancesis a peer-reviewed, online only, open access journal of the American Society of Hematology (ASH), the world's largest professional society concerned with the causes and treatment of blood disorders.

Blood Advances is a registered trademark of the American Society of Hematology.

SOURCE Blood Advances

http://www.bloodadvances.org

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Study: Cryopreservation Associated with Loss of Quality in Donor Stem Cell Products - PRNewswire

Bone Marrow Stem Cells Comments Off on Study: Cryopreservation Associated with Loss of Quality in Donor Stem Cell Products – PRNewswire | September 4th, 2020

MIKE TYSON has been doing the rounds to physically prepare for his sensational boxing comeback aged 54.

Tyson, who retired in 2005, has a whole new diet and cardio regime as well as going through a "weird" stem cell treatment.

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The former heavyweight king announced plans to make a return to the ring to compete in exhibition bouts for charity, and has been training hard ahead of his comeback.

He is set to face fellow legend Roy Jones Jr on November 28.

Speaking to rapper LL Cool J on the Rock the Bells Radio show on SiriusXM, Tyson explained the methods he is using to get back into fighting shape, as he revealed: "Really I would just change my diet and just do cardio work.

"Cardio has to start, you have to have your endurance to go and do the process of training.

"So something to do is get in cardio, I would try and get two hours of cardio a day, make sure you get that stuff in. Youre gonna make sure youre eating the right food.

"For me its almost like slave food. Doing what you hate to do but doing it like its nothing. Getting up when you dont want to get up.

"Thats what it is. Its becoming a slave to life.

"Being a slave to life means being the best person you can be, being the best you can possibly be, and when you are at the best you can possibly be is when you no longer exist and nobody talks about you. Thats when youre at your best."

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WHAT IS STEM CELL TREATMENT USED FOR?

Stem cell transplants are carried out when bone marrow is damaged or isnt able to produce healthy blood cells.

It can also be used to replace damaged blood cells as the result of intensive cancer treatment.

Here are conditions that stem cell transplants can be used to treat:

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Tyson's return to training for the first time in 15 years has been aided by stem-cell research therapy, that has left him feeling like a "different person".

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition that usually takes the form of a bone marrow transplantation.

Tyson was asked whether that meant if his white blood had been spun and then put back in, to which he replied: "Yes. As they took the blood it was red and when it came back it was almost transfluid (sic).

"I could almost see through the blood, and then they injected it in me.

"And Ive been weird ever since, Ive got to get balanced now."

Having previously claimed he feels in the best shape of his life, Tyson revealed he will be ready and raring to fight again.

He said: "My mind would belong to somebody that disliked me enough to break my soul, and I would give them my mind for that period of time.

"Six weeks of this and Id be in the best shape Ive ever dreamed of being in. As a matter of fact, Im going through that process right now. And you know what else I did, I did stem-cell research."

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During his reign as champion, Tyson would wake up at 4.30am to run before later heading to the gym where he would do 10-12 rounds of boxing mixed in with an array of muscles exercises.

His diet consisted of 3000-4000 calories of carbohydrates and proteins which helped fuel his training sessions.

Tyson, still the youngest heavyweight champion of all time at 20, retired with a record of 50-6-2 and remains one of the most celebrated punchers of all time.

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How Mike Tyson is in such incredible shape at 54 thanks to new diet, cardio and weird stem cell tre - The Irish Sun

Bone Marrow Stem Cells Comments Off on How Mike Tyson is in such incredible shape at 54 thanks to new diet, cardio and weird stem cell tre – The Irish Sun | September 4th, 2020

Could gene therapy provide a solution to HIV? A new research project aims to find out.

The National Institutes of Health(NIH) has backed researchers at the University of Southern California and the Fred Hutchison Cancer Center with a five-year, $14.6 million grant to develop a gene therapy that could potentially control HIV without the need for daily medications. Most HIV patients take a well-regimented cocktail of medications each day to control the virus. This therapy could change that. According to an announcement from the Keck School of Medicine at USC, the goal will be to develop a therapy that prepares patients for a stem cell transplantation using their own cells with little to no toxicity, engineers their own stem cells to fight HIV and stimulates those cells to quickly produce new and engineered immune cells once they're reintroduced into the patient. The hematopoietic stem cell transplants, also known as bone marrow transplants, have been used to treat some blood cancers. The idea is to infuse an HIV patient withhealthy donor blood stem cells that can grow into any type of blood or immune cell.

The gene therapy strategy has been inspired by three cases where leukemia patients who also had HIV received blood stem cell transplants from donors who also carried a mutation that confers immunity to HIV. The mutation was in the CCR5 gene, which encodes a receptor that HIV uses to infect immune cells and is present in about 1 percent of the population, USC said.

The program will engineer blood cells to remove CCR5 from a patient's own stem cells.That will be combined with other genetic changes so that the progeny of engineered stem cells will release antibodies and antibody-like molecules that block HIV.

In addition to the potential gene therapy treatment, researchers are also assessing whether or not CAR-T treatments will benefit HIV patients. Researchers from Harvard University developed a Dual CAR T-cell immunotherapy that can potentially help fight HIV infection. First reported by Drug Target Review, the HIV-specific CAR-T cell is being developed to not only target and eliminated HIV-infected cells, but also reproduce in vivo to enable the patients to fight off the infection. HIVs primary target it T cells, which are part of the bodys natural immune response.

Todd Allen, a professor of Medicine at Harvard Medical School, said the Dual CAR-T cell immunotherapy has so far provided a strong, long-lasting response against HIV-infection while being resistant to the virus itself.

According to the report, theDual CAR T cell was developed through the engineering of two CARs into a single T cell. Each of the CARs contained a CD4 protein that allowed it to target HIV-infected cells and a costimulatory domain, which signaled the CAR T cell to increase its immune functions. As DTR reported, the first CAR contained the 4-1BB co-stimulatory domain, which stimulates cell proliferation and persistence, while the second has the CD28 co-stimulatory domain, which increases its ability to kill infected cells.

To protect the CAR-T cells from HIV, the team added the protein C34-CXCR4, which prevents HIV from attaching to and infecting cells. When that was added, the researchers found in animal models that the treatment was long-lived, replicated in response to HIV infection, killed infected cells effectively and was partially resistant to HIV infection.

Still, other researchers are looking to those rare individuals who are infected with HIV but somehow on their own are able to suppress the virus without the need for any treatment. Researchers have sought to replicate what this small percentage of patients can naturally do in other patients who require those daily regimens of medications. Through the sequencing of the genetic material of those rare individuals, researchers made an interesting discovery.

The team discovered large numbers of intact viral sequences in the elite controllers chromosomes. But in this group, the genetic material was restricted to inactive regions, where DNA is not transcribed into RNA to make proteins, MedNewsToday reported.

Now the race is on to determine how this can be replicated and used to treat the nearly 38 million people across the globe who have been diagnosed with HIV.

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New HIV Gene Therapy, CAR-T Treatments Could be on the Horizon for Patients - BioSpace

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The independent Data Safety Monitoring Board has completed its first interim analysis of data from a Phase 3 clinical trial evaluating Mesoblast Limited's (MESO -0.3%) remestemcel-L, an allogeneic mesenchymal stem cell product derived from bone marrow, in COVID-19 patients with moderate-to-severe acute respiratory distress syndrome (ARDS).

Based on preliminary results from 30% of targeted enrollment, the Board recommends that the study continue unchanged.

A total of three interim analyses for stopping accrual early for efficacy or futility will be done (30%, 45% and 60% of total target of randomized patients). Enrollment should be completed in Q4.

The primary endpoint is all-cause mortality within 30 days of randomization. A key secondary endpoint is days alive off mechanical ventilation within 60 days of randomization.

According to the company, remestemcel-L is believed to have immunomodulatory properties to counteract the cytokine storms that are implicated in various inflammatory conditions by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

SA Contributor Avisol Capital Partners is Bullish on the stock.

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Late-stage study of Mesoblast cell therapy in COVID-19 to continue as is - Seeking Alpha

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Compiled by Gabi Zietsman | Health24

04 Sep 2020, 02:45

Two hikers are going to great heights to increase awareness of blood disorders, and the urgent need for bone marrow donors in South Africa.

In a symbolic hike up the country's highest peak in the Drakensberg range, adventurer and bone marrow donor Clayton Coetzee and expert mountaineer and author Gavin Raubenheimer will be tackling Mafadi from 7 to 9 September in honour of those who have helped save the lives of countless people suffering from blood disorders.

Bone marrow donation is close to my heart as one of my dearest friends got sick with Acute Myeloid Leukaemia (AML) several years ago," says Coetzee. "Its then when I heard about the SA Bone Marrow Registry and the life-saving work that they do, and I decided to sign up as a donor."

READ | Could smoking lead to this blood disorder?

Increase in cases

Blood cancer is one of the most common of these disorders and affects children the most, while other blood disorders include non-Hodgkin lymphoma (NHL).

Unfortunately, according to the Search Coordinator for the SA Bone Marrow Registry (SABMR) Alicia Venter, these diseases have increased in the last decade 45% in NHL cases and 26% in leukaemia cases.

"While recommended, prevention efforts, such as lifestyle changes, tend to be less effective for hematologic malignancies than for other cancers, which makes a blood stem cell transplant a patients only hope for survival," says Venter.

In order to be a suitable bone marrow donor, your human leukocyte antigen (HLA) needs to match someone in need. HLAs are genes in a human's DNA that help regulate immunity and affect whether or not a recipient's body will reject a transplant.

READ MORE | Bone marrow transplants less risky now

Need more non-white donors

Finding a match, however, isn't as easy as swiping on a dating app and SAMBR has a serious lack of diversity in the donor database. Currently, there are only about 74 000 local donors on the South African Bone Marrow Registry.

In South Africa, there is a dire need for donors of colour," explains Venter.

"When it comes to matching HLA types, a patients ethnicity plays an important role as HLA markers are inherited. Some ethnic groups have more complex tissue types than others, therefore finding a match is most likely to come from someone of the same ethnic group."

'As easy as giving blood'

The hike is supposed to be symbolic of the uphill battle that faces those suffering from blood disorders, including finding a suitable donor to increase their chances of survival. Besides the gruelling experience, SAMBR will also be doing a cheek swab drive at the same time in Agulhas, Western Cape, and Musina, Limpopo, to help boost donor registrations.

According to Coetzee, it's easy to be registered as a donor all it takes is a cheek swab. If you do match with someone, it's "almost as easy as giving blood".

If a match is found, a donor will undergo a full medical exam to look for any exclusionary factors like obesity, HIV status, other chronic conditions and viral infections. Once cleared, the donor goes on a five-day treatment of injections to increase the number of stem cells in the bloodstream.

On the fifth day, the donor will be admitted to a hospital and connect to a cell separator machine, where the bone marrow donation would be made. The collected samples then has 72 hours to be transplanted to the receiving patient.

In South Africa, doctors will seldom collect bone marrow straight from the source.Possible side effects to receiving the injections may include headache, bone pain and flu-like symptoms.

I want people to know that blood diseases can affect anyone, regardless of ethnicity or gender. Extending beyond our boundaries or comfort zones like climbing Mafadi can be hard, but imagine the indelible difference the act of becoming a donor can have on someone elses life and their loved ones, says Coetzee.

You can follow the hikers' journey onSAMBR's Facebook page.

If you are between the ages of 18 and 45 and want to become a donor, contact the SABMR on021 447 8638 oremail:donors@sabmr.co.za.For more info and how to donate, visit their website.

READ MORE | Leukaemia survivor stories

Image credit: Pixabay

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There is a dire need for 'donors of colour' in the fight against blood disorders - Health24

Bone Marrow Stem Cells Comments Off on There is a dire need for ‘donors of colour’ in the fight against blood disorders – Health24 | September 4th, 2020

Gamida Cell Ltd. (Nasdaq: GMDA), an advanced cell therapy company committed to cures for blood cancers and serious blood diseases, today announced that it will host a two-part virtual miniseries in September focused on key topics related to omidubicel, an advanced cell therapy in Phase 3 clinical development as a potentially life-saving treatment option for patients in need of a bone marrow transplant. The webcasts will take place on Friday, September 11, 2020, and Wednesday, September 23, 2020, both at 1:00 p.m. ET.

The miniseries topics are as follows:

In May, Gamida Cell reported that its Phase 3 study of omidubicel met its primary endpoint, demonstrating a highly statistically significant reduction in time to neutrophil engraftment, a key milestone in recovery from a bone marrow transplant. Gamida Cell expects to present the full data set, including secondary endpoint data, at a medical meeting in the fourth quarter of 2020. The company also expects to begin submitting the biologics license application for omidubicel to the U.S. Food and Drug Administration (FDA) on a rolling basis in the fourth quarter of 2020. Omidubicel is the first bone marrow transplant product to receive Breakthrough Therapy Designation from the FDA and has also received Orphan Drug Designation in the U.S. and EU.

Each webcast will be available on the Investors & Media section of the Gamida Cell website at http://www.gamida-cell.com. A replay of the webcast will be available about two hours after the event, for approximately 90 days.

About Omidubicel

Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplant solution for patients with hematologic malignancies (blood cancers). In both Phase 1/2 and Phase 3 clinical studies (NCT01816230 and NCT02730299), omidubicel demonstrated rapid and durable time to engraftment and was generally well tolerated.1,2 Omidubicel is also being evaluated in a Phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937). The aplastic anemia investigational new drug application is currently filed with the FDA under the brand name CordIn, which is the same investigational development candidate as omidubicel. For more information on clinical trials of omidubicel, please visit http://www.clinicaltrials.gov.

Omidubicel is an investigational therapy, and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.

About Gamida Cell

Gamida Cell is an advanced cell therapy company committed to cures for patients with blood cancers and serious blood diseases. We harness our cell expansion platform to create therapies with the potential to redefine standards of care in areas of serious medical need. For additional information, please visit http://www.gamida-cell.com or follow Gamida Cell on LinkedIn or Twitter at @GamidaCellTx.

Cautionary Note Regarding Forward Looking Statements

This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to the anticipated timing of data disclosures and regulatory filing submissions, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the ongoing global COVID-19 pandemic and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Gamida Cells Annual Report on Form 20-F, filed with the Securities and Exchange Commission (SEC) on February 26, 2020, and other filings that Gamida Cell makes with the SEC from time to time (which are available at http://www.sec.gov), the events and circumstances discussed in such forward-looking statements may not occur, and Gamida Cells actual results could differ materially and adversely from those anticipated or implied thereby. Any forward-looking statements speak only as of the date of this press release and are based on information available to Gamida Cell as of the date of this release.

References

1Horwitz M.E., Wease S., Blackwell B., Valcarcel D. et al. Phase I/II study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide. J Clin Oncol. 2019 Feb 10;37(5):367-374. 2Gamida Cell press release, Gamida Cell Announces Positive Topline Data from Phase 3 Clinical Study of Omidubicel in Patients with High-Risk Hematologic Malignancies, issued May 12, 2020. Last accessed August 31, 2020.

Investor Contact:Jaren Irene Madden

[emailprotected]1-617-286-6264

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Gamida Cell Announces Two-Part Virtual Miniseries Focused on Omidubicel to Take Place in September - Global Banking And Finance Review

Bone Marrow Stem Cells Comments Off on Gamida Cell Announces Two-Part Virtual Miniseries Focused on Omidubicel to Take Place in September – Global Banking And Finance Review | September 4th, 2020

Featured image: A human baby, just days after its birth, with the umbilical cord stump still attached. Photo: Wikimedia Commons/Evan-Amos, Public Domain

My patient, a man in his 70s, sat a few feet away from me in a clinic room at our cancer centre. His wife was by his side, both literally and emotionally she was his touchstone, his connection to the normal life he led before his leukemia diagnosis. I noticed they tended to wear outfits that even complemented each other, as if their sartorial choices had harmonized and become intertwined along with their affection over the 40 years of their marriage. Their choice for the day: grey sweatshirts declaring their allegiance to the hapless Cleveland Browns.

He had weathered the slings and arrows of the chemotherapy we used to treat his cancer during a five-week hospital stay, and now was in a tenuous remission. We talked about the next steps in his treatment, which ranged from giving him a break, to more chemotherapy, to considering the most aggressive intervention we could offer a bone marrow transplant.

The phrase bone marrow transplant was a bit of a misnomer, though. While we could wipe out any residual leukemia in his bone marrow with high-dose chemotherapy and replace his fresh bone marrow from a healthy person, we may not be able to find a good bone marrow match. Another potential option: We could use umbilical cord blood from a newborn, which is rich in the stem cells normally found in the bone marrow, and which recent studies have shown may not need to match as closely as is necessary for a marrow donor. Hearing this, my patients wife interjected.

Our daughter is pregnant, and her due date is next month. She started, glancing at my patient as he nodded his head in agreement. She wanted us to ask if she should save the babys cord blood in case he needs it for a transplant.

I explained to them that the babys cord blood was unlikely to be a close enough match to my patient, as my patients daughter would only be a half-match for him, and her baby less than that. My patient then asked me a question I have been hearing more and more over the years: Should my daughter save the cord blood in case our grandbaby needs it, in case he or she develops cancer?

Indeed, in the US, the practice of storing umbilical cord blood is steadily on the rise. Banking cord blood in case a bone marrow transplant is needed in the future is appealing on so many levels. The umbilical cord attaching the developing fetus to its mothers placenta is rich in those juicy bone marrow stem cells that are so effective at making the blood components. Coming from an infant at the time of birth, they should be uncorrupted by cancer (emphasis on theshould, as well see in a moment). Cord blood is also easy to collect: At the time of delivery, after the cord is cut, the remaining blood in that cord is milked out into a collection bag. That bag is then kept in a freezer until the time comes, if ever, when it is needed and can be infused as a transplant.

The cost of using commercial cord blood banking companies, however, can be substantial. Upfront charges with whats called an enrollment fee can range from $1,500 to $3,500. On top of that, a yearly storage fee is assessed, with the total amount for 18-20 years of storage cresting $5,000 in some cases.

Brochures for these companies line Plexiglas display cases in obstetrics offices, with pamphlets exhorting nervous, expectant parents to protect their baby from the medical evils that lie ahead. What better source for a transplant than a childs own, pure stem cells, harvested at a time years before that child ever developed cancer? But cost aside, is the effort even worth it for the risk that a child may one day develop a cancer and need a future transplant?

Taking a couple of things into consideration

To answer this question, we need to take a couple of things into consideration. First, what is the likelihood of a child developing a cancer, and then needing a transplant to treat that cancer? Astudy conducted by the Center for International Blood and Marrow Transplant Research attempted to figure this out. They first identified the cancers for which transplantation could potentially be needed. For people aged 0-19 years (the length of time a cord blood would be kept banked) leukemia was the most common, followed by lymphoma, neuroblastoma, brain tumors, and sarcomas. Cancer in children and adolescents are rare all told, the incidence rate in the US for all of these cancers combined is about 12 per 100,000 children per year. Its horrible if its your child who develops cancer, but pediatric cancer is still an uncommon event.

The next conclusion is based on the likelihood that these cancers would not be eradicated by chemotherapy and/or radiation therapy and would require an allogeneic transplant that is, one that uses stem cells taken from a genetically matched donor and the assumption that everyone could identify a sibling or brother from another mother transplant and was healthy enough to undergo the procedure. The authors estimated that the incidence rate of transplant for children and adolescents was a little over 2 per 100,000 per year in the US during their first two decades of life. Analyzed another way, the probability a child will need a transplant by the time he or she reaches age 20 is 0.04%.

The lifetime chance of getting struck by lightning is similar, at about 1 in 3,000, or 0.033%.

Would you pay thousands of dollars for a medication right now, in the event that sometime in your life you may be struck by lightning, and that medication may help you survive the lightning strike?

Seems excessive to me.

Also Read: Crosstalk: How Two Modest Heroes Won the Battle Against Childhood Leukaemia

Is cord blood really as pure as we think?

A second way of determining the value of cord blood banking in case a child develops cancer is to consider whether that cord blood is really as pure as we think. The most common childhood cancer through age 19 is leukemia, with an annual incidence rate of 4.7 per 100,000 children in the US. Could it be possible that the leukemia was present at some small level even at birth, years before the child was diagnosed with leukemia?

One approach to studying this would be to screen every newborn for leukemia. Given the incidence rate of childhood leukemia, this would mean subjecting over 21,000 babies to a blood test for every case of future leukemia identified.

Its difficult to justify that type of monumental screening effort to answer a research question about the origins of leukemia. A more reasonable approach would be to identify children who have leukemia, and try to determine whether they had it when they were born.

But how to go about obtaining a blood sample from a birth that occurred years earlier? A group of clever scientists from the UK and Germany thought the answer might be found in something called Guthrie cards. Robert Guthrie was a microbiologist working at the Roswell Park Cancer Institute in Buffalo, New York, in the 1950s when his niece was diagnosed with phenylketonuria (PKU), an inherited deficiency in the enzyme necessary to metabolize the amino acid phenylalanine. If caught early enough, an infants diet can be modified so that the effects of the deficiency are minimised. If not, the condition can lead to developmental defects and mental disability.

Guthries niece was not so lucky.

This, and having a child of his own with cognitive delays, motivated Guthrie to devote his career to detecting preventable childhood diseases. He developed a test for PKU that could be performed when a drop of blood from a finger prick or heel stick was applied to filter paper on a card. It was successfully piloted in Newark in 1960, and by 1963, 400,000 infants had been tested in 29 states. Testing spread around the country, and across the pond.

And hospital laboratories kept those Guthrie cards for years after a child was born.

A startling discovery

The scientistsfound three children with acute lymphocytic leukemia (more common in children than AML, whereas the opposite is true in adults) who had the same chromosome mutation associated with their leukemias a translocation of chromosomes 4 and 11. After obtaining permission from the parents of these children, the scientists then searched laboratory repositories to find the Guthrie cards stored there from when the children were born.

They used a PCR-specific lab test for this translocation on the dried blood still remaining on the childrens Guthrie cards, and were able to detect the chromosome abnormality for all three children from a blood drop obtained months or years before the leukemia was diagnosed. In another, similar study, the same group of scientists was able to detect chromosome evidence of leukemia in 9 of the 12 Guthrie cards obtained from children who diagnosed with leukemia between two and five years later.

The leukemia was there all along, even prior to birth in these children, waiting years in some cases to rear its ugly head. And if the leukemia was measurable on a genetic level in their blood, it was almost certainly present in their cord blood. Banking cord blood from these children would have preserved those juicy, healthy stem cells, but also probably cells already corrupted by genetic abnormalities that would lead to leukemia again, if the cells were re-infused into a child as a transplant years later.

Getting back to the question: Is the cost and effort of banking cord blood worth it for the risk that a child may one day develop a cancer and need a future transplant?

I didnt think so when my three children were born.

But I did have their cord blood collected and I donated it to be stored for use through theBe The Match programme, in case a complete stranger needs it. So that one day, my children could be the brothers from another mother, or sister from another mister me being the mister!

And so that one day, my patients wont have to forego potentially curative treatments for their leukemias because they cant find an adequate donor.

Mikkael Sekeres is the director of the Leukemia Program at the Cleveland Clinic and the author of When Blood Breaks Down: Life Lessons from Leukemia, from which this article is adapted.

This article was originally published on The MIT Press Reader.

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The Fallacy of Banking Umbilical Cord Blood for Your Baby - The Wire Science

Bone Marrow Stem Cells Comments Off on The Fallacy of Banking Umbilical Cord Blood for Your Baby – The Wire Science | September 3rd, 2020

A young girl with an extremely rare blood disorder has been dealt a huge blow after her bone marrow donor her only match in the world pulled out at the last moment.

After developing a pinprick rash on her back, eight-year-old Evie Hodgson from Yorkshire in the UK was diagnosed with deadly aplastic anaemia in May, a blood disease in which the body doesnt produce enough blood cells.

The schoolgirl was due to undergo a bone-marrow transplant this month that would save her life but her donor called as she was preparing for the operation.

Evies parents Andy and Tina, and younger brother William, were sadly not a match, but they did find a 10/10 match, with the anonymous donor agreeing to the transplant.

But as she prepared for the transplant by having one of her ovaries removed and undergoing dental work, on August 14, just days before the planned surgery, the donor pulled out.

RELATED: Mum stranded in Ukraine after surrogate gives birth

Now her parents have set up a Facebook page to help find a new hero, calling on people to get tested and see if they are a match.

Initially it seemed that Evie had been lucky as a match for the transplant was found quickly and the procedure was planned to take place in August, a post on the Evie Needs a Hero Facebook page reads.

Only a few weeks prior to the planned transplant date Evies one and only 10/10 donor has pulled out of donating his stem cells. This news was totally unexpected and her family and friends are devastated.

In just over a week, the page has amassed almost 20,000 followers, many who are undergoing testing to see if they can help Evie.

RELATED: Heartbreaking pandemic impact on babies

Mum Tina said the family were devastated by the huge blow adding they had no idea why the donor changed their mind everything is confidential.

Evie has already been through so much, she told The Metro. She thought she had a donor and now she doesnt.

The donor pulling out is quite hard-hitting but from our point of view we just want to raise awareness of the stem cell register.

Initially doctors thought Evie may have leukaemia when she became sick during coronavirus lockdown earlier this year.

Then they were given the devastating diagnosis of aplastic anaemia.

Evie needs a stem cell transplant from a compatible donor to survive and has recently undergone an immunosuppressant course of treatment while the search for a new stem cell donor continues.

I need this transplant to save my life, Evie says in a video on the Facebook page. Please sign the register to help save my life.

Continue the conversation @RebekahScanlan | rebekah.scanlan@news.com.au

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Girls heartbreaking plea after her only bone marrow donor pulls out - NEWS.com.au

Bone Marrow Stem Cells Comments Off on Girls heartbreaking plea after her only bone marrow donor pulls out – NEWS.com.au | September 3rd, 2020

A distraught family in the UK has made an urgent plea after their little girl, who has a rare blood disorder, had her only bone marrow donor pull out at the last minute.

Just as she got prepared for the bone marrow transplant, Evie Hodgsons donor pulled out - devastating her family.

Her mother is now worried about the eight year olds future, as the chances of finding another donor are extremely slim.

In fact, theyre so slim that doctors are trying to find another course of treatment for Evie.

This is despite the fact that finding a stem cell transplant from a compatible donor is the best hope of curing the little girl.

Evie, from North Yorkshire, has deadly aplastic anaemia which was diagnosed after she developed a rash on her back that didnt fade.

She was found to have low blood platelet levels which doctors worried was leukaemia.

A biopsy found that Evie didnt have cancerous cells and she was diagnosed with the anaemia - her parents told she would need a bone marrow transplant.

A worldwide search was launched to find a donor after it was found that her family wasnt a match.

The search concluded after an anonymous donor was found who was a 10/10 match.

Next, they began to prepare for the transplant, which included both dental work and the removal of an ovary.

On August, the family got the devastating news that the donor had, in fact, pulled out.

We were devastated, it was a huge blow, mum Tina said.

We have no idea why the donor changed their mind. Everything is confidential.

Evie has already been through so much. She thought she had a donor and now she doesnt.

The donor pulling out is quite hard-hitting but from our point of view we just want to raise awareness of the stem cell register.

Its so easy to be a donor. Its just like giving blood, but you could save a childs life.

Some people dont even know they could be a match.

Its so easy to join the register but only about 1 per cent of the UK population is registered.

The eight-year-old is now to undergo an immunosuppressant course of treatment.

This is while the search for a donor continues.

The family has made a Facebook group to update people on her journey and to also raise awareness within the community.

The condition Evie has is life-threatening, Tina said.

She wont survive without a transplant.

Thats why we are desperately appealing for any many people as possible to register as a stem cell donor.

I need this transplant to save my life, Evie added.

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'Huge blow' as girl's only bone marrow donor in the world pulls out at last minute - 7NEWS.com.au

Bone Marrow Stem Cells Comments Off on ‘Huge blow’ as girl’s only bone marrow donor in the world pulls out at last minute – 7NEWS.com.au | September 3rd, 2020

One of the best performers on theS&P/ASX 200 Index(ASX: XJO) in August was the Mesoblast limited(ASX: MSB) share price.

The biotechnology companys shares recorded a stunning 40.5% gain during the month.

Investors were scrambling to buy the biotechnology companys shares in August due to positive developments relating to its remestemcel-L product candidate.

Remestemcel-L, also known as RYONCIL, is being developed as a treatment for paediatric steroid-resistance acute graft versus host disease (paediatric SR-aGvHD).

SR-aGvHD is an area of extreme need, particularly in vulnerable children under 12 years old where there is no approved therapy. It occurs in approximately 50% of patients who receive an allogeneic bone marrow transplant (BMT) and has a very high mortality rate.

Remestemcel-L is an investigational therapy comprising culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor.

It is administered to patients in a series of intravenous infusions and is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in SR-aGvHD. This is by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

In August the company hadits meeting with the Oncologic Drugs Advisory Committee (ODAC) of the U.S. FDA to discuss remestemcel-L as a potential treatment for paediatric SR-aGvHD.

The good news was that after some initial doubts, the ODAC was supportive of remestemcel-L and gave it the thumbs up.

While this doesnt necessarily guarantee that the U.S. FDA will approve it on 30 September, its opinions have a big sway on product approvals for cancer drugs. In light of this, the odds are certainly in Mesoblasts favour later this month.

I think Mesoblast is an exciting company and well worth keeping a close eye on.

However, due to its current valuation, I would class it as a hold and would sooner be a buyer of CSL Limited (ASX: CSL) shares.

I think they are trading at a more attractive level after a recent pullback.

When investing expert Scott Phillips has a stock tip, it can pay to listen. After all, the flagship Motley Fool Share Advisor newsletter he has run for more than eight years has provided thousands of paying members with stock picks that have doubled, tripled or even more.*

In this FREE STOCK REPORT, Scott just revealed what he believes are the 3 ASX stocks for the post COVID world that investors should buy right now while they still can. These stocks are trading at dirt-cheap prices and Scott thinks these could really go gangbusters as we move into the new normal.

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The Mesoblast share price rocketed 40% higher in August: Is it too late to invest? - Motley Fool Australia

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The European Society for Blood and Marrow Transplantation (EBMT), Europe's collaborative peer network of professionals working in the field of stem cell transplantation and cellular therapy, announced today the results of the phase III RACE trial during EBMTs virtual 46th Annual Meeting. Preliminary data show that adding Eltrombopag to standard immunosuppressive treatment is safe and increases response rates in patients with Severe Aplastic Anaemia (SAA).

SAA is a condition in which the bone marrow does not produce enough new blood cells. It is a rare, yet potentially fatal disease which can be treated with bone marrow transplantation or, for patients who are not eligible to receive a transplantation, with immunosuppressive treatment. The most commonly used immunosuppressive regimen includes horse ATG (hATG) in combination with Cyclosporine A (CsA). However, about 35% of patients do not respond to treatment or eventually relapse.

Eltrombopag is a thrombopoietin receptor agonist that was developed to stimulate thrombopoiesis (production of platelets), but it was subsequently shown to restore trilineage haematopoiesis. A previous single-arm study showed that adding Eltrombopag to standard immunosuppressive treatment appeared to improve the response rate as compared to the use of hATG plus CsA alone. The first results of the randomised controlled RACE trial now confirm that adding Eltrombopag to standard immunosuppression leads to significantly higher response rates compared to standard immunosuppressive treatment alone.

The RACE trial is sponsored by the EBMT with the financial support of Novartis and Pfizer. Professors. Rgis Peffault de Latour (Head of the French Reference Center for Aplastic Anemia and PNH, Saint-Louis Hospital, and University of Paris) and Antonio M. Risitano (Federico II University, Naples, and Head of Hematology and the BMT Unit, Ospedale Moscati, Avellino, Italy) served as Principal Investigators of the study, and they designed the study together with Professor Carlo Dufour (Head of the Hemato Oncology and Stem Cell Transplantation Department. G.Gaslini Childrens' Research Hospital, Genova, Italy). Under the energetic and efficient coordination of Sofie Terwel, the trial was successfully conducted by the RACE study team at the EBMT Clinical Trial Office. The study was presented by Prof. Peffault de Latour at the presidential symposium of EBMT's virtual Annual Meeting and was granted the Van Bekkum Award, the most prestigious EBMT award for the best abstract submitted to the physician's programme.

The international, investigator-driven, open-label, phase III, randomised trial evaluated 197 patients with SAA. Patients were aged 15 years or older, had acquired SAA, and had not received prior immunosuppressive treatment. Patients were randomised to receive either standard immunosuppression (hATG 40 mg/kg x4d and CsA 5 mg/kg/d) or standard immunosuppression + Eltrombopag at the dose of 150 mg/d from day +14 until 6 months (or 3 months, in case of early complete response). The primary endpoint of the study is complete response (CR) at 3 months, with CR being defined as haemoglobin 100 g/L, neutrophils 1.0 g/L and platelets 100g/L, according to standard international criteria.

It was shown that three months after treatment start, patients who received the combination of hATG, CsA plus Eltrombopag had a significantly higher complete response rate compared to patients treated with hATG and CsA alone. These higher response rates were sustained at 6 months. Moreover, Eltrombopag was generally well-tolerated, with a comparable occurrence of adverse events in the two treatment arms. This trial also shows that in this rare disease, large randomised trials can successfully be run in collaboration with many expert centres in Europe.

"Eltrombopag is registered in Europe for second line treatment of aplastic anaemia, so it is only available to patients who cannot receive bone marrow transplantation and have failed immunosuppressive treatment" explains Prof. Peffault de Latour. Prof. Risitano states: "The RACE trial data shows that eltrombopag increased response rates for nave SAA patients who are not eligible for hematopoietic stem cell transplantation. The RACE study team is continuing to follow up the trial participants up to two years and furthermore aims to set up a long-term follow-up study to monitor the effectiveness and safety of Eltrombopag up to ten years.". "The EBMT Clinical Trial Office is already actively working on this new project, which likely will provide the final evidence about the benefit of using triple therapy as initial treatment for Severe Aplastic Anemia." concludes Prof. Dufour.

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EBMT trial shows improvements in treatment of Severe Aplastic Anaemia - Science Codex

Bone Marrow Stem Cells Comments Off on EBMT trial shows improvements in treatment of Severe Aplastic Anaemia – Science Codex | September 3rd, 2020