Category Archives: Stem Cell Therapy

Nabiha Saklayen, CEO and co-founder of Cellino

Today, Cellino Biotech, an autonomous cell therapy manufacturing company, announced an $80 million Series A financing round led by Leaps by Bayer along with8VC, Humboldt Fund, and new investors including Felicis Ventures and Khosla Ventures, that could fix a problem holding the biotech industry back. Cellino plans to expand access to stem cell-based therapies with a goal to build the first autonomous human cell foundry in 2025.

To understand why this matters, you have to look at the history of drug development. During the last 20 years, drug development has moved from making small molecules and chemicals, such as aspirin, that can have an impact on biology to biologicals like proteins, antibodies, and most recently RNA vaccines. The next frontier of development is using engineered human cells as the drugs themselves.

Six years ago, Leaps by Bayer, the investment arm of the German pharmaceutical giant Bayer AG, decided to take a risk on a small startup pioneering what they believed could be transformative technology for human health. Leaps by Bayer was one of the investors that placed a big bet on a company called BlueRock Therapeutics with a $225 million Series A financing, which at the time was the largest Series A ever made in biotech.

What was the technology that inspired Leaps by Bayer to make such a large investment in 2016? It was the ability to engineer human stem cells that could treat many diseases. Six years later, BlueRock Therapeutics is doing a Phase 1 clinical trial to treat patients with advanced Parkinsons disease using stem cell-derived neurons.

Despite this tremendous progress and new companies entering the market, there is still something holding back progress. It is the ability to reliably manufacture enough stem cells to meet rising demands for research and industry.

Imagine being able to take out your own cells, called autologous therapy, and engineering them to fight cancer. Then, putting the cells back into your body to fight cancer. One of the benefits of using your own cells with this therapy is that your immune system is less likely to attack them. Or imagine being able to take somebody else's cells, called allogeneic therapy, and engineering them to perform a particular function before injecting them into patients.

Autologous and allogeneic therapy are the future of drug development. When Leaps by Bayer invested in BlueRock Therapeutics it created the first disruption of the industry. Leaps by Bayer were the pioneers who jump started this industry in the early days, says Saklayen.

Now, Leaps by Bayer is leading another disruption of the industry, but this time, it is focused on clearing a big bottleneck. The bottleneck of stem cell engineering happened because the entire process was manual and very complicated, says Saklayen. It usually involved a scientist sitting at a bench looking at these cells by eye and then making decisions about which cells were good or bad. And then the scientists would go in and try to remove the bad cells with a pipette tip.

Through Cellino, the industry will have reliably manufactured stem cells at scale. Cellino uses machine learning, artificial intelligence (AI), and laser technology to automate cell therapy manufacturing. Cells are created in a closed cassette format, which allows thousands of patient samples to be processed in parallel in a single facility. The end result, these cassettes of human cells, can be used to treat patients.

Our vision is to build a Cellino foundry. I envision it will look much like a server room. But each shelf has a cassette of cells being manufactured in an autonomous manner, says Nabiha Saklayen, CEO and co-founder of Cellino.

Leaps by Bayers mission is to invest in paradigm-shifting technologies that provide long- term answers to some of todays biggest challenges, said Juergen Eckhardt, MD, Head of Leaps by Bayer. We believe that artificial intelligence-driven manufacturing is the next important inflection point towards industrializing cell therapies, which undoubtedly are one of the core technologies to advance biotech from treatment to prevention or disease reversal. Cellinos truly transformative technology to autonomously manufacture stem cell- based therapies fits precisely with our ambition to regenerate lost tissue function for millions of patients.

The potential of stem cell-derived medicines is enormous with many applications, including the treatment of Parkinsons disease, diabetes, and heart disease. This is the frontier of drug development that is poised to change the industry.

Thank you to Lana Bandoim for additional research and reporting in this article. Im the founder of SynBioBeta, and some of the companies that I write about, including Leaps by Bayer, are sponsors of the SynBioBeta conference and weekly digest.

Read more here:
This Stem Cell Manufacturing Startup Just Raised An $80 Million War Chest To Revolutionize Medicine - Forbes

RANDY HUTCHINSON| Better Business Bureau

The FDA says that stem cell products may offer the potential to treat many medical conditions and diseases for which few alternative treatments exist, but almost all of them have yet to be proven to be effective or safe. That hasnt stopped unscrupulous medical professionals and other promoters from touting them as miracle cures.

Stem cells are sometimes called the bodys master cells because they develop into blood, brain, bones and the bodys other organs. Stem cells that come from bone marrow or blood are routinely used to treat cancer and other disorders of the blood and immune system. But other uses, including treating COVID-19, have not been properly studied under an FDA Investigational New Drug Application, which includes providing sufficient data from human clinical testing to help evaluate a products potential risks.

The FDA cites these potential safety concerns for unproven treatments:

There are safety risks even with your own stem cells and contamination can occur if cells are manipulated after removal.

The FTC and Georgia Attorney General sued the co-founders of the Stem Cell Institute of America for allegedly targeting seniors with bogus claims that its therapy could treat arthritis, joint pain and other orthopedic ailments. The agencies said the company also claimed its stem cell therapy is comparable or superior to surgery, steroid injections and painkillers. A related company trained chiropractors and other healthcare practitioners in making similar claims. They also hosted free educational seminars for consumers at which they promoted injections that cost approximately $5,000 per joint, with many patients receiving multiple injections.

This wasnt the FTCs first enforcement action against deceptive stem cell therapy claims. In 2018, a California physician and his companies settled with the FTC over claims their amniotic stem cell therapy could treat Parkinsons disease, autism, macular degeneration, cerebral palsy, multiple sclerosis, heart attacks and a host of other serious ailments. The defendants earned at least $3.3 million offering injections that cost up to $15,000.

The only stem cell products approved by the FDA for use in the United States consist of blood-forming stem cells derived from umbilical cord blood. Theyre approved for limited use in patients with disorders that affect the production of blood.

In bringing the most recent action, the Acting Director of the FTCs Bureau of Consumer Protection said, At best, the use of unproven products or therapies can cost consumers thousands of dollars without affording them any results. At worst, it can be harmful to their health.

If youre considering a stem cell treatment, the FDA says to make sure its FDA-approved or being studied under an Investigational New Drug Application. The FTC and BBB offer these additional tips:

Randy Hutchinson is the president of the Better Business Bureau of the Mid-South. Reach the BBB at 800-222-8754.

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Beware of unproven stem cell therapies - The Jackson Sun

Significance

Osteoarthritis (OA) is a chronic disease affecting millions of people worldwide with no curative solution. In the present study, we developed a minimally invasive injectable system using amnion membrane (AM) from the human placenta as a carrier for fat tissue-derived stem cells (adipose-derived stem cells [ADSCs]) to treat OA. Both AM and ADSCs are rich sources of bioactive molecules that can target the sites of inflammation and reduce the inflammation-driven articular cartilage damage. Our study demonstrated the disease-modifying and regenerative potential of AM hydrogel, a comparable regenerative and disease-modifying effect of AM hydrogel and ADSCs, and the synergistic effect of AM with ADSCs in regenerating cartilage and attenuating OA.

Current treatment strategies for osteoarthritis (OA) predominantly address symptoms with limited disease-modifying potential. There is a growing interest in the use of adipose-derived stem cells (ADSCs) for OA treatment and developing biomimetic injectable hydrogels as cell delivery systems. Biomimetic injectable hydrogels can simulate the native tissue microenvironment by providing appropriate biological and chemical cues for tissue regeneration. A biomimetic injectable hydrogel using amnion membrane (AM) was developed which can self-assemble in situ and retain the stem cells at the target site. In the present study, we evaluated the efficacy of intraarticular injections of AM hydrogels with and without ADSCs in reducing inflammation and cartilage degeneration in a collagenase-induced OA rat model. A week after the induction of OA, rats were treated with control (phosphate-buffered saline), ADSCs, AM gel, and AM-ADSCs. Inflammation and cartilage regeneration was evaluated by joint swelling, analysis of serum by cytokine profiling and Raman spectroscopy, gross appearance, and histology. Both AM and ADSC possess antiinflammatory and chondroprotective properties to target the sites of inflammation in an osteoarthritic joint, thereby reducing the inflammation-mediated damage to the articular cartilage. The present study demonstrated the potential of AM hydrogel to foster cartilage tissue regeneration, a comparable regenerative effect of AM hydrogel and ADSCs, and the synergistic antiinflammatory and chondroprotective effects of AM and ADSC to regenerate cartilage tissue in a rat OA model.

Osteoarthritis (OA) affects the entire synovial joint, including the articular cartilage, synovium, and subchondral bone (1). In the United States alone, 27 million people are affected by this disease, and the associated healthcare cost has been estimated at more than $185 billion annually (2). Recent studies have shown that inflammation and its induced catabolism play an important role in promoting OA symptoms and accelerating the disease (3). The best-known and critical inflammatory mediators are tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1) expressed during the early stages of OA (4, 5). The catabolic effects of proinflammatory cytokines lead to reduced cartilage cellularity, changes in chondrocyte functions, and further breakdown of cartilage extracellular matrix (ECM) (6, 7). Both nonsurgical and surgical therapies are currently being used in OA treatment which provide temporary relief but have failed to treat OA pathogenesis.

Since inflammation is the key factor in OA progression, developing novel therapies that can suppress inflammation and promote regenerative pathways may prevent/delay OA progression and thus hold promise for OA treatment. Along this line, a variety of studies investigated the potential role of adipose-derived stem cells (ADSCs) in treating OA (3). The therapeutic properties of ADSCs are multifaceted (7, 8) as they contain several antiinflammatory and chondroprotective agents which inhibit inflammation, suppress immune recognition, and reduce apoptosis and dedifferentiation of chondrocytes (911). Recently, the beneficial effects of ADSCs on OA treatment via intraarticular injections have been studied in different animal models (1214) as well as clinical trials (15, 16). Although stem cell therapy has achieved promising results in OA treatment, the long-term therapeutic application of stem cells remains limited. Previous studies have shown that stem cells provide a temporary/early-stage effect rather than prolonged effectiveness in treating OA, indicating the need for higher cell numbers and multiple cell injections. The short-term effects of stem cells are mainly due to limited long-term cell survival/retention, extensive cell death and poor cellular function, and inadequate cellular distribution following injection in the target site (17). To overcome these challenges, large doses of cells and multiple injections have been tried; however, these approaches are not economically viable and are associated with the risk of cell overexpansion (17).

To overcome these limitations, delivery systems capable of sustaining the survival and maintaining functions of implanted cells are needed to stimulate endogenous regeneration through interactions of transplanted cells and the host tissue. In our previous study (18), we developed an injectable amnion membrane (AM)based hydrogel as a stem cell delivery system. These AM hydrogels supported cellular functionalities such as cell viability, proliferation, and stemness. Also, our studies showed the ability of both AM hydrogels and AM hydrogelADSC combinations to provide an immunomodulatory and chondroprotective environment in an invitro osteoarthritic model (18). AM is the innermost layer of placental tissue which is easily accessible and includes collagens (types I, III, IV, V, and VI), fibronectin, laminin, proteoglycans, and hyaluronan. AM has been shown to suppress the expression of potent proinflammatory cytokines, such as IL-1 and IL-1 and decrease matrix metalloproteinase (MMP) levels through the expression of natural MMP inhibitors present in the membrane. AM also contains IL-1Ra, a receptor antagonist for IL-1, a proinflammatory cytokine that has been shown to up-regulate in OA (19). Placenta also plays an important role in reducing host immune response in case of allogeneic transplantation as it possesses the unique function of preventing the fetal allograft from being rejected (19). The feasibility of using AM as a carrier system for chondrocytes which promoted cell proliferation, cellular phenotype invitro, and cartilage regeneration invivo has been demonstrated in various studies (20, 21). However, the major limitation of these studies is the use of AM in the form of sheets, which would require invasive surgical procedures. To overcome the surgery-associated complications, minimally invasive therapies using micronized AM in saline were developed which also have demonstrated efficacy in attenuating OA invivo (22, 23). However, intraarticular injections experience rapid clearance of therapeutics, which may limit efficacy and produce nonsignificant effects (24). Thus, localization and prolonged retention are critical for a sustained release of therapeutics to act efficiently with minimal injections.

The overall goal of this study was to improve the efficacy of stem cell therapy to treat OA using our previously designed cell-protective and cell-supporting injectable AM hydrogel as a stem cell delivery system. We investigated the potential of AM hydrogel as a delivery system for ADSCs and evaluated the effect of AM hydrogels with and without ADSCs to prevent inflammation and cartilage degeneration and promote cartilage tissue regeneration in a collagenase-induced knee OA rat model.

In total, 376 proteins were identified in the AM gel by liquid chromatographymass spectrometry (LC-MS) (Dataset S1). The important proteins which might impart the beneficial effects of amnion for tissue regeneration include collagen, laminin, fibronectin, small leucine-rich proteoglycans (SLRPs), proteoglycans, and tissue inhibitors of metalloproteinases (TIMPs) (19). The proteins identified in AM gel were categorized according to their predominant location and functions using the Human Proteome Reference Database and UniProt database (Fig. 1). The identified proteins were found to be largely located in the extracellular environment of AM tissue (Fig. 1A). The predominant functions of these proteins were to facilitate ECM and cytoskeleton organization (EC + SC + SM: >85%; Fig. 1B). To further identify the biological implications of these proteins observed in AM gel, the proteins were associated with their Gene Ontology (GO) terms. (Dataset S2). The top five GO terms for the biological process of protein observed in AM gel were extracellular matrix organization (GO:0030198), cell adhesion (GO:0007155), collagen fibril organization (GO:0030199), neutrophil degranulation (GO:0043312), and cornification (GO:0070268)/keratinization (GO:0031424) (Fig. 1C). Table 1 summarizes the list of proteins identified in AM gel related to cartilage tissue regeneration.

Relative abundance of proteins identified in the AM. Pie chart representing the distribution of all identified proteins in the AM according to their subcellular location (A) and function (B). Assignments were made according to their primary location and function as reported in the Human Protein Reference (http://www.hprd.org/) and UniProt (https://www.uniprot.org/) databases. Primary subcellular location: CP, cytoplasm and cytosol; CS, cytoskeleton; EC, extracellular environment; ER, endoplasmic reticulum; G, Golgi apparatus; M, mitochondrion; MB, integral to membrane and plasma membrane; N, nucleus or nucleolus; R, ribosome; V, vesicles including cytoplasmic vesicle, endosome, and lysosome. Function: EC, ECM structural constituent; I, immune response; M, metabolism and energy pathways; RN, regulation of nucleotide; SC, structural constituent of cytoskeleton; SM, structural molecule activity; ST, signal transduction; T, transporter activity; O, other functions including apoptosis, cell cycle, cell growth, motor activity, organization, extracellular ligands, and unknown. The value was rounded off to one decimal place. (C) Top five GO annotations for biological processes of the detected proteins in AM gel.

The identification of proteins related to cartilage tissue regeneration in AM

Pathogenesis of OA in the rat knee joints occurred after 1 wk of collagenase II injection. The hematoxylin and eosin (H&E) images indicated that the sham knee did not show signs of synovial inflammation (Fig. 2A). The collagenase-injected group showed a high degree of synovial inflammation (Fig. 2B, black arrows) with an increase in the number of synovial lining cell layers and infiltration of inflammatory cells. The Safranin O image reflected smooth joint surfaces of the sham (Fig. 2C), while the collagenase-injected group showed erosion of the articular cartilage showing signs of OA development (Fig. 2D, black arrow). The knee diameter data showed that the OA group had significantly higher joint swelling on day 7 compared to the sham group (Fig. 2E).

H&E staining images of rat knee joint: (A) Sham group with saline injection, (B) OA group treated with collagenase enzyme. Safranin-O staining images of rat knee joint: (C) Sham group with saline injection, (D) OA group treated with collagenase enzyme. (E) Joint swelling evaluation of sham and OA groups. n = 6 showing mean and SD (****P<0.0001). (Scale bars: A and B, 200 m; C and D, 2 mm.)

After 1 wk of collagenase injection, the rats were divided into four groups: control (phosphate-buffered saline [PBS]), ADSC, AM gel, and AM-ADSC.

Joint swelling analysis at day 7 after collagenase injection showed a significant increase in joint diameter compared to day-0 groups (before collagenase injection), indicating synovitis of the knee joint. No significant difference was observed in the groups at days 3 and 7 posttreatment. At days 14 and 21 posttreatments, knee swelling of the AM-ADSC group was lower compared to control, AM, and ADSC groups. At 28 d posttreatment, ADSC (0.8 0.3, P<0.05), AM gel (0.5 0.1, P <0.0001), and AM-ADSC (0.4 0.1, P <0.0001) treatment groups showed a significant decrease in joint diameter compared to the control group (1.4 0.8). Importantly, the knee diameter in the AM-ADSC group was found to be significantly lower than ADSC (P <0.001) and AM groups (P <0.05), indicating decreased synovial inflammation in the combination group AM-ADSC (Fig. 3).

Joint inflammation for different treatment groups (n = 6) showing mean and SD (****P<0.0001, ***P<0.001, **P<0.01, *P < 0.05). All treatments groups showed significant decrease in joint swelling 28 d posttreatment compared to control group. The combination group (AM-ADSC) showed significant decrease in joint swelling compared to ADSCs alone and AM gel alone.

The cytokine profiling analysis of serum showed an increase in intercellular adhesion molecule 1 (ICAM-1), leptin, selectin, and monocyte chemoattractant protein-1 (MCP-1) and a decrease in TIMP-1 7 d after collagenase treatment (Fig. 4 AE). The level of TIMP-1 was found to significantly increase on day 28 in AM-ADSC (39,536 pg/mL 2,277) compared to control (28,485 pg/mL 4,087, P <0.0001) and ADSC (26,520 pg/mL 3,416, P <0.0001) groups (Fig. 4A). No significant difference was found in ICAM-1 and MCP-1 levels from day 3 to 14 posttreatment. On day 21 the AM-ADSC group (5,778 pg/mL 549) showed a significant decrease (P < 0.05) in ICAM-1 compared to the control group (8,641 pg/mL 1,439). A significant decrease in MCP-1 levels was also noted in AM-ADSC group (5,089 pg/mL 810) compared to control groups (7,748 pg/mL 304, P < 0.0001) after day 21. Both AM and ADSC groups showed a comparable decrease in the levels of MCP-1, ICAM-1, leptin, and selectin and an increase in TIMP-1, though not significant compared to control on day 28. The AM-ADSC group further showed a significant reduction of ICAM- 1, leptin, and MCP-1 levels compared to all other groups on day 28 (Fig. 4 B, C, and E), indicating a synergistic antiinflammatory effect (SI Appendix, Table S1). Selectin level was found to decrease for all groups compared to the control group from day 21; however, the effect was not significant (Fig. 4D). An increase in up-regulation of other proinflammatory cytokines was not detected as they were below the detection limit by the enzyme-linked immunosorbent assay (ELISA) multiplex array.

Cytokine profiling of serum isolated from whole blood from different groups: (A) TIMP-1, (B) ICAM-1, (C) leptin, (D) selectin, and (E) MCP-1; n = 6 showing mean and SD (****P<0.0001, ***P<0.001, **P<0.01, *P<0.05).

Raman spectroscopic changes of serum were measured by quantifying the integrated peak area in the spectral region 1 (SR1, 1,372 cm1 to 1,599 cm1) and region 2 (SR2, 1,601 cm1 to 1,776 cm1). Upon normalization of the area of these two spectral regions SR1 and SR2 with the integrated peak area of phenylalanine band at 1,004 cm1, it was observed that the normalized integrated areas for both the regions increased upon collagenase treatment (day 7 after collagenase injection) compared to day-0 serum samples. As presented in Fig. 5, the normalized integrated area in SR1 decreased in all the treatment groups with a significant decrease in the AM-ADSC group (2.4 0.6) compared to the control group (7.5 0.5, P < 0.0001) and AM gel group (5.5 1.8, P < 0.05). The normalized integrated area in SR2 also showed a similar trend with a significant reduction in all treatment groups compared to the control group. It is also important to note that the AM-ADSC group for 28-d treatment showed a significant decrease in the peak area (4.4 0.7) compared to both the ADSC group (9.9 1.4, P < 0.05) and AM gel group (10.3 1.7, P < 0.05), indicating a synergistic antiinflammatory effect.

Normalized peak area of (A) region 1 (B) region 2; mean and SD with n = 6 (****P<0.0001, ***P<0.001, *P<0.05).

Fig. 6 shows the gross appearance of the cartilage plateau in all groups. The sham group (Fig. 6A) showed a smooth, glossy cartilage surface. The control group (Fig. 6B) showed cartilage lesions, erosion, and fissures, indicating severe damage. ADSC groups (Fig. 6C) showed improvement compared to the control group; however, the lesions were still prominent. The AM group (Fig. 6D) also showed signs of erosion which was less prominent compared to the ADSC group and control group. The AM-ADSC (Fig. 6E) groups showed slightly damaged cartilage surface which was closer to the sham group, indicating a synergistic chondroprotective effect.

Gross appearance of cartilage surface after 4 wk posttreatment showing smooth surface in (A) sham group, erosion in (B) control group and (C) ADSC group, less erosion in (D) AM group, and fewer signs of lesion in (E) AM-ADSC group with closer appearance to sham group. Yellow arrows indicate the cartilage damage.

Control animals at 4 wk showed pronounced synovial inflammation with an increase in the number of synovial lining cell layers (Fig. 7A, black arrows), and lesions and areas of erosion were prominent along with diminished Safranin O staining for both femoral and tibial surface, suggesting the loss of proteoglycan content (Fig. 7E). ADSC treatment reduced the synovial inflammation (Fig. 7B) and preserved the loss of proteoglycan content of cartilage ECM, but the synovial inflammation, lesion, and areas of erosion were still evident (Fig. 7 B and F). In contrast, histological analysis of AM gel (Fig. 7 C and G) and AM-ADSC (Fig. 7 D and H) treated joints showed a significant reduction in synovial inflammation. Both AM gel and AM-ADSC groups showed smooth cartilage surfaces with no lesions and strong Safranin O staining. However, the AM-ADSC group showed more prominent Safranin O staining with a consistently more uniform cartilage tissue compared to the AM gel group. Safranin O staining of sagittal sections was used to assess the degenerated cartilage matrix area caused by the OA phenotype (Fig. 7I). The calculated total degeneration area was found to be 35.1 13.3% in the control group. AM gel groups showed a significant decrease in the total degenerated area (24.4 7.6%) compared to the control group (P < 0.05), indicating the chondroprotective potential of AM gel. ADSC-injected groups showed a significant decrease in total degeneration area which was found to be 21 6.6% compared to the control group (P < 0.05), indicating a comparable chondroprotective effect. Furthermore, treatment with the AM-ADSC (6.9 3.6%) observed a significant reduction in cartilage degeneration compared to control (P < 0.0001), ADSC group (P < 0.05), and AM group (P < 0.05) and the degenerated area was comparable to the sham (6.6 2.2%), demonstrating the synergistic chondroprotective effect.

H&E staining images of rat knee joints treated with (A) control, (B) ADSC, (C) AM hydrogel, and (D) AM-ADSC after 4 wk. Safranin O staining of rat knee joint treated with (E) control, (F) ADSC, (G) AM gel, and (H) AM-ADSC. (I) Percentage joint degenerated area calculation. n = 6 showing mean and SD (***P<0.001, **P<0.01, *P<0.05). (Scale bars: AD, 200 m; EH, 2 mm.)

Stem cell therapy has emerged as a potential therapy to provide a more reliable and curative solution to treat OA. However, the effectiveness of stem cell therapy is limited by difficulties in achieving the right therapeutic doses within the target site. In view of this, we developed an injectable AM hydrogel as a stem cell delivery system with an aim to localize stem cells at the target site, maintain cellular functionalities and synergistically reduce inflammation, and activate regenerative pathways, thereby attenuating OA progression. The AM hydrogel has been characterized in our previous studies to understand the swelling, degradation, and rheological behavior. Our previous study showed that the stiffness of AM hydrogels ranged between 120 and 1,600 Pa, indicating that the matrix stiffness can be tuned by varying the protein concentration (18). The physical properties of hydrogels play an important role in regulating stem cell fate (25). The AM hydrogels were shown to support ADSC functionalities as softer hydrogels with lower matrix stiffness <1 kPa are known to maintain stem cell viability, proliferation, and stemness (26). Softer hydrogels have also been shown to prevent transplanted cell death after cell delivery, improving the therapeutic efficacy of stem cell delivery at the target site after injection (27). Also, the AM hydrogels exhibited a shear-thinning property which is an important criterion for translating an injectable hydrogel as highly viscous or shear thickening material that may block the syringe while injecting (18). Also, the potential of AM with or without stem cells to present antiinflammatory and chondroprotective effects was demonstrated in an invitro OA model (18). In the present study, a comprehensive proteomic analysis of AM gel was done to understand its composition which may regulate tissue regeneration. LC-MS characterization of AM revealed the presence of proteins such as collagen, laminin, fibronectin, SLRPs, and proteoglycans. Collagen is the most abundant ECM family in the articular cartilage, including mainly collagen II along with IX, X, XI, VI, XII, and XIV collagen (28), which regulates the structurefunction relationship of the cartilage tissue. The presence of collagen VI may play an important role in promoting chondrocyte proliferation (29). Other proteins found in AM such as collagen XII are known to interact with collagen VI, resulting in up-regulation of tissue regeneration (30). The presence of keratin could also be beneficial as studies have shown its role in increasing cellular adhesion and inducing polarization of inflammatory M1 macrophages to antiinflammatory M2 phenotype (31). PLEC is a large cytoskeletal protein that regulates signaling from the extracellular environment to the cell nucleus (32). In cartilage, the OA-associated single-nucleotide polymorphism correlates with differential expression of PLEC and with differential methylation of PLEC CpG dinucleotides (33). Intact vimentin intermediate filament network contributes to the maintenance of the chondrocyte phenotype (34). Heparan sulfate proteoglycans bind to many proteins that regulate cartilage homeostasis. Agrin expression is decreased in OA, and exogenous agrin enhanced cartilage differentiation (35). SLRPs have important effects on cell behavior by interacting with collagens to modulate fibril formation and binding various cell-surface receptors and growth factors. Alterations in the distribution and production of SLRPs could lead to the development of OA (36). TIMPs are the primary endogenous inhibitors of MMPs. TIMP-3 has the broadest inhibition spectrum as it inhibits several members of a disintegrin and metalloprotease (ADAM) and ADAM with thrombospondin motifs (ADAMTS) (37). The proteomic profiling indicates that the AM gel used in our study still retains a rich source of important proteins, which makes it a highly effective biomaterial for OA treatment and cell delivery applications.

A collagenase-induced OA rat model was used to evaluate the effectiveness of AM hydrogel with or without ADSCs to attenuate OA. This is an established model and has been predominantly used to investigate the mechanisms underlying joint damage (38). Collagenase treatment directly digests the collagen from cartilage ECM, resulting in pain, changes in the synovial membrane and subchondral bone, and degeneration of articular cartilage (39). Similar features were observed in our study, which showed inflammation in the synovial membrane and degeneration of cartilage in a collagenase-injected group, thereby reproducing some of the main features associated with onset and development of OA in humans (40). The dosage of collagenase (500 U) was chosen based on a previous study that compared two different dosages (250 U and 500 U) of collagenase to induce OA in the rat model and found 500 U was more effective in inducing inflammation and cartilage degeneration (38).

An early time point of week 1 was chosen to study the effect of the treatments in inhibiting inflammation and cartilage degeneration (38). Intraarticular injection of amnion suspension in a monosodium iodoacetate (MIA) OA model has been previously shown to reduce joint swelling on day 14 (0.7 mm). However, an increase in the joint swelling was noticed on day 21 (1.1 mm) (41). In the present study, all three treatment groups, ADSC (0.8 0.3, P<0.001), AM gel (0.5 0.1, P <0.0001), and AM-ADSC (0.4 0.1, P <0.0001), significantly reduced joint swelling compared to the control group (1.4 0.8) at day 28. The joint swelling was found to comparable in the AM gel group and ADSC group. Moreover, the AM-ADSC group significantly reduced joint swelling compared to other groups. This demonstrated the antiinflammatory properties of AM gel alone and synergistic advantages of combining AM with ADSC in inhibiting inflammation, an early indication of OA onset and progression. This was corroborated by the cytokine profiling wherein AM hydrogel and ADSC showed a comparable decrease in inflammation. AM-ADSC significantly reduced inflammation markers such as MCP-1, leptin, and ICAM-1 and increased TIMP-1 compared to the control group and other treatment groups. MCP-1 is a chemokine produced by synovial cells which attract monocytes to facilitate the OA immune response, leading to clinical symptoms such as redness, swelling, and pain (42). ICAM-1 is a critical mediator of inflammation that mediates activation, migration of leukocytes, and adhesion of antigen-presenting cells to T lymphocytes and has been found to be higher in OA patients (43). Willett etal. (23) previously showed that intraarticular injection of micronized AM reduced MCP-1 levels (132 113 pg/mL) after 21 d in a medial meniscal transection (MMT)induced OA model in rats. However, another study using amnion suspension for OA treatment in an MIA model did not find any significant reduction in MCP-1 or increase in TIMP-1 levels compared to the saline group (38). The present study showed a decrease in the inflammatory markers in AM gel group in a collagenase-induced OA model.

The biomolecular changes in the serological composition were then evaluated by Raman spectroscopy (RS). RS can be used to follow arthritic changes in serum and synovial fluids by determining the changes in the protein secondary structure (44, 45). Studies have also shown the effectiveness of RS in detecting protein changes in inflammatory conditions (45). The spectra regions 1 and 2 used in the present study to detect the changes in serological composition have been previously used to study serum samples from arthritic patients (45). The study showed an increase in the peak area of regions 1 (70 a.u., arbitary unit P < 0.05) and 2 (55 a.u., P < 0.05) in serum samples from arthritis patients compared to the healthy individuals (region 1, 65 a.u.; region 2, 50 a.u.). SR1 reflects signatures from the amide II band and SR2 reflects the changes in the amide I peaks. An increase in SR1 and SR2 peak area indicates more disordered protein secondary structure with altered electrostatic interactions as evident from RS analysis of serum and synovial fluid samples from arthritic patients (44, 45). In the present study, the RS spectra profile showed a significant decrease in the peak area of SR2 in all the three treatment groups compared to control at day 28 posttreatment, which can be attributed to less-disordered protein secondary structure. Overall, the RS observation corroborates the cytokine profile data indicating a comparable effect of AM hydrogel and ADSCs in reducing inflammation and a synergistic antiinflammatory property of AM-ADSC and the unique advantages of combining AM with ADSC to reduce inflammation in an OA environment.

Macroscopic and microscopic evaluations of the treatment groups showed degenerated cartilage tissue in the control group. Compared to the control group, AM hydrogel showed a disease-modifying and regenerative effect by significantly decreasing cartilage degeneration. The disease-modifying and regenerative effect was also found to be comparable in AM and ADSC groups. The disease-modifying and regenerative capability of AM hydrogel was further enhanced upon the addition of ADSCs, indicating a synergistic effect of AM and ADSC. Previous studies have shown that injection of MSC suspension fails to engraft with the cartilage tissue, indicating a short-lived effect of stem cells (46, 47). Sato etal. reported that only a small number of stem cells was detected within the OA cartilage 1 wk posttreatment, which were found to disappear after 5 wk (48). Studies have shown that 90% of cells usually die postinjection at the target site due to physical stress, hypoxia, and inflammation (49). This shows that a single injection of stem cells may not be enough to improve the OA condition, indicating the need for periodic injections (50). While stem cells injected as a suspension do not engraft into the cartilage, MSCs encapsulated in a matrix such as hyaluronic acid (HA) appear to engraft and contribute significantly to cartilage repair. Studies have shown that combining HA and stem cells improves the quality of cartilage compared to cells and HA alone (48, 51, 52). However, recent studies have demonstrated a modest benefit of HA in OA treatment (53). Thus, to develop an alternative solution, AM has been used in the present study as a cell delivery system for OA treatment. It is evident from the present study that ADSCs showed some positive response in reducing inflammation and cartilage degeneration using the collagenase-induced OA model. However, the effect is not as significant as in the combination group, indicating an advantage of combing AM with ADSCs. The use of AM in attenuating OA has also been shown in different studies. The efficacy of intraarticular injection of micronized AM suspension was investigated in a rat MMT model 24 h after MMT surgery and found smaller lesions and fewer defect volume compared to a saline-treated group 21 d postinjection (23). Saline-treated joints showed an average incidence of 2.8 0.2 erosion, 2.4 0.4 lesion, and an average lesion volume of 0.00725 0.005 mm3, whereas the AM suspension showed significant reduction in erosion sites (1.2 0.374) and no lesions (23). Another study using amnion suspension (total joint score, 13.7 0.2) 7 d after OA induction showed no significant improvement in the joint scores compared to the control group (total joint score, 13.5 0.4) (41) in an MIA-induced OA model. Another study demonstrated a dose-dependent benefit of particulate AM along with umbilical cord tissue in attenuating OA. It was noticed that at 4 wk postinjection 100 g/L of particulate AM/UC (umbilical cord) significantly reduced both lesion area and percent lesion area compared to control and 50 g/L of AM/UC group (54). In the present study AM gel (24.4 7.6%) even at a lower concentration of 6 g/L significantly reduce cartilage degeneration compared to control groups (35.1 13.3%) in a collagenase-OA model. The addition of ADSCs further improved the potential of AM gel (6.9 3.6%) to attenuate OA progression. This indicated the advantages of using an AM gel at a lower concentration over particulate AM at a higher concentration in suspension.

The findings of the present study thus indicate that the AM hydrogel can foster cartilage tissue regeneration. The study also demonstrated a comparable effect of AM hydrogel and ADSCs in regenerating the cartilage tissue and synergistic antiinflammatory and chondroprotective properties of AM-ADSC. This indicates the unique advantages of combining AM with ADSC to reduce inflammation and slow down cartilage degeneration and regenerate cartilage tissue in an OA environment. The invivo study also validated our previous study which demonstrated a synergistic antiinflammatory and chondroprotective effect of AM-ADSC in an invitro OA model (18). In addition, since inflammation is a key regulator of OA progression, and as of now there is no solution to modulate the inflammatory processes and prevent OA, the use of AM gel alone or in with ADSC may provide disease-modifying effects to control the disease (3). However, further studies will be needed to evaluate the degradation of AM hydrogel invivo, release kinetics and retention profile of stem cells, and the paracrine effect of cells within the target site.

Cell therapy is widely used to address the current unmet needs of complex degenerative diseases such as OA. However, the lack of an ideal delivery system resulted in inconsistent outcomes, indicating the need for a more reliable strategy. This study demonstrated the feasibility of using a biomimetic injectable hydrogel using AM as a delivery system for ADSCs to attenuate OA and regenerate cartilage tissue in a rat OA model. Our study showed the potential of AM hydrogels for disease modification and regenerating the cartilage tissue. Both AM and ADSC groups showed comparable disease-modifying and cartilage tissue regeneration effects. In addition, the study also confirmed the synergistic effect of the combination group (AM-ADSC) for disease modification and cartilage tissue regeneration. Future studies need to investigate the mechanism of the synergistic effect of AM and ADSCs and the translation potential of AM hydrogels with and without ADSCs using larger animal models.

Discarded, deidentified placental tissues were obtained after getting approval from the institutional ethical committee (University of Connecticut Health). The isolation methods were performed in accordance with the experimental guidelines and regulations approved by the Institutional Review Board, University of Connecticut Health (study number IE-08-310-1). The amnion hydrogel was developed according to a previously published protocol (18). Briefly, AM was decellularized, solubilized in a pepsin solution, and neutralized to form a hydrogel. The neutralized AM was diluted to the desired final AM concentration (6 mg/mL) with PBS on ice. AM was then characterized by LC-MS to evaluate the complex protein composition of AM.

AM was suspended in 5% sodium dodecyl sulfate in 0.1 M TrisHCl (pH 8.5), subjected to sonication, and prepared for downstream proteomics analysis using the S-trap midi column technology (Protifi, LLC). Proteins were subjected to Cys reduction, alkylation using iodoacetamide, and trypsin digestion using Protifis instructions. Eluted tryptic peptides were desalted using Pierce C18 peptide desalting spin columns (P/N 89851) using the manufacturers instructions, dried to completion using a Labconco speedvac concentrator, and resuspended in 0.1% formic acid in water prior to mass spectrometry analysis.

The peptides generated from AM were independently analyzed using ultrahigh-performance LC coupled to tandem MS (UPLC-MS/MS) on a Dionex Ultimate 3000 RSLCnano UPLC system coupled to a Q Exactive HF mass spectrometer (Thermo Scientific). About 1.25 g of each desalted peptide were directly loaded onto a 75-m 25-cm nanoEase m/z Peptide BEH C18 analytical column (Waters Corporation) and separated using a 3-h reversed-phase UPLC gradient at a flow rate of 300 nL/min. Eluted peptides were directly ionized into the Q Exactive HF using positive polarity electrospray ionization. MS/MS data were acquired using a data-dependent Top15 acquisition method. All raw data were searched against the full UniProt Homo sapiens reference proteome (UP000005640, last updated 29 June 2020) using the Andromeda search engine embedded in the MaxQuant software platform (v1.6.43.10) (55, 56). The following modifications were used: fixed carbamidomethyl Cys and variable oxidation of Met, acetylation of protein N termini, deamidation of Asn and Gln, and peptide N-terminal Gln-to-pyro-Glu conversion. Enzyme specificity was set to trypsin, minimum peptide length was set to 5, and all peptide- and protein-level identifications were filtered to a 1% false discovery rate following a target-decoy database search. Label-free quantitation was achieved using the MaxLFQ feature in MaxQuant. All other parameters were kept at default settings. Search results were uploaded into Scaffold v5 (Proteome Software) for visualization and further analysis. All detected proteins were searched and categorized according to their primary location and function using the Human Protein Reference (http://www.hprd.org/) and UniProt (https://www.uniprot.org/) databases. Pie charts were created based on the quantified amounts of detected proteins. GO terms for the biological processes were searched by UniProt database.

ADSCs were isolated from 6- to 8-wk-old Sprague-Dawley rats in accordance with the experimental guidelines and regulations approved by the University of Connecticut Health Center Institutional Animal Care and Use Committee (IACUC)approved protocol. The isolation and characterization by flow cytometry were done according to our previously optimized protocol (18).

Animal experiments were approved by the IACUC at the University of Connecticut Health. Male Sprague-Dawley rats (8 wk old) were used for the study and divided into two groups (sham and collagenase-injected group). Briefly, rats were anesthetized by isoflurane (4% isoflurane for anesthesia induction, 2% for maintenance) and an intraarticular injection was performed with the use a 29-gauge needle inserted through the patella ligament into the joint space of the right knee. They received two injections (day 0 and 3) according to the group. The collagenase-injected group (n = 6) received about 500 U of collagenase type II (Sigma-Aldrich) in 100 L of normal saline after filtering through a 0.22-m membrane (38). The sham group (n = 6) received 100 L of normal saline.

A week after the first collagenase injection, the OA-induced rats were divided into four groups according to the treatments they would receive: control (PBS), ADSCs, AM gel (6mg/mL), and AM-ADSCs combination (n = 6 each group). Using a 29-gauge needle inserted through the patella ligament into the joint space of the right knee, all the OA knees received 100-L injections according to the specific treatment of the group. About 1 106 ADSCs were reconstituted in PBS and AM gel for the ADSC and AM-ADSC groups, respectively.

The knee diameters were measured to determine the extent of joint swelling with a manual caliper. Results were presented as the difference in knee diameter (ipsilateralcontralateral) (35).

Whole blood was collected from the saphenous vein at regular time points. Blood was then allowed to clot for 30 min and the serum was separated by centrifugation at 1,500 g for 10 min. The levels of cytokines in the serum were measured using the Quantibody Rat Cytokine Array 2 multiplex ELISA kit that quantitatively measured 10 rat inflammatory factors: ICAM-1, interferon , IL-1, IL-6, IL-10, leptin, L-selectin, MCP-1, TIMP-1, and TNF-alpha (RayBiotech). All ELISA procedures were performed according to the manufacturers protocols.

Raman measurements were carried out from the serum samples at an excitation wavelength of 785 nm using a free-space custom-built inverted Raman microspectroscopy system as described previously (57). Briefly, the Raman spectrometer consisted of a 193-mm focal length spectrograph (Shamrock 193i; Andor) equipped with a thermoelectric cooled charge-coupled device camera (iDus DU420A-BEX2-DD; Andor). Both excitation and collection were performed using the same 60 objective with the numerical aperture of 1.1 (LUMFLN60XW; Olympus). Serum was isolated and placed onto a quartz coverslip (Ted Pella, Inc.). The average power at the sample was held constant at 25 mW; the integration time for a single Raman measurement was 30 s, and two accumulations were averaged. The raw Raman spectra were preprocessed by removing cosmic rays, subtracting Raman signals from quartz coverslip and smoothing. The area of peaks in region 1 (1,372 cm1 to 1,599 cm1), region 2 (1,601 cm1 to 1,776 cm1) were calculated and normalized with respect to the area of phenylalanine peak at 1,004 cm1 (48) using Origin Pro software.

Animals were killed 4 wk after treatment. The cartilage surface was exposed by carefully removing the surrounding soft tissue including the joint capsule and meniscus. The effect of different treatment groups on osteoarthritic joints was examined macroscopically and photographed using a digital camera.

The dissected knee joints were fixed with 10% neutral-buffered formalin and subsequently decalcified, embedded in paraffin, and cut into 5-m sections. Specimen slides were then deparaffinized and hydrated by soaking them sequentially for the time indicated in xylene, ethanol, and deionized water. For H&E, sections were stained with hematoxylin Harris (Sigma-Aldrich) and counterstained with eosin (Sigma-Aldrich). For Safranin O, sections were stained with Weigerts iron hematoxylin (Sigma-Aldrich) working solution and fast green solution (Sigma-Aldrich) then counterstained with Safranin O solution (Sigma-Aldrich). Slides were viewed with the aid of the light microscope after being cleared with alcohol and xylene (Sigma-Aldrich). Articular surface areas of sagittal joint sections (areas stained red with Safranin O on the articular surface of the tibia and the femur) were quantified using ImageJ image analysis software. Areas of degeneration where there was no red staining by Safranin O were measured using ImageJ and the percent degeneration at the joint was measured using the following formula:%Degeneration=DegeneratedAreasTheoreticalHealthyArticularSurfaceArea*100.

All statistical analysis was done using GraphPad Prism 6. A two-sided ANOVA with 95% confidence interval with Tukeys means comparison was run in GraphPad Prism 6 to evaluate intergroup differences of percent total degenerated areas. For joint swelling, cytokine analysis, and Raman spectroscopic analysis a oneway ANOVA was run with a Tukeys post hoc test to assess statistical significance between groups.

All study data are included in the article and/or supporting information.

We gratefully acknowledge the quantitative proteomics analysis conducted by Dr. Jeremy L. Balsbaugh and Dr. Jennifer C. Liddle of the UConn Proteomics & Metabolomics Facility, a component of the Center for Open Research Resources and Equipment at the University of Connecticut. We are also thankful to Dr. Zhifang Hao, Research Histology core, UConn Health for helping out with the histology studies. We also gratefully acknowledge funding from NIH DP1AR068147 and NIH T32 AR079114.

Author contributions: M.B., L.S.N., and C.T.L. designed research; M.B., J.L.E.I., H.-M.K., R.B., M.B., N.N., R.P., L.S.N., and C.T.L. performed research; M.B., S.S., T.O., R.P., L.S.N., and C.T.L. analyzed data; and M.B., S.S., R.P., L.S.N., and C.T.L. wrote the paper.

Competing interest statement: A patent titled Injectable Amnion Hydrogel as a Cell Delivery System has been filed and published on behalf of the inventors, C.T.L., L.S.N., and M.B. L.S.N. has competing financial interest with Soft Tissue Regeneration/Biorez. C.T.L. has the following competing financial interests: Mimedx (a company that makes amnion-based biologics), Alkermes Company, Biobind, Soft Tissue Regeneration/Biorez, and Healing Orthopaedic Technologies-Bone.

Reviewers: J.G., Johns Hopkins University; and R.L., University of Chicago Division of the Biological Sciences.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2120968119/-/DCSupplemental.

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Injectable amnion hydrogel-mediated delivery of adipose-derived stem cells for osteoarthritis treatment - pnas.org

HOUSTON--(BUSINESS WIRE)--InGeneron, Inc., a clinical stage biotechnology company, announced the publication of a succinct scientific review of regenerative cell therapy, commonly called stem cell therapy, to treat orthopedic indications. This newly released paper, titled Why and how to use the bodys own stem cells for regeneration in musculoskeletal disorders: a primer, was published in the Journal of Orthopaedic Surgery and Research (J Orthop Surg Res 17, 36 (2022): https://doi.org/10.1186/s13018-022-02918-8). The publication provides an approachable overview of stem cell biology and clarifies common misconceptions about adipose-derived regenerative cells (ADRCs) including vascular-associated pluripotent stem cells (vaPS cells). The authors emphasize the ability of therapies using ADRCs to readily fit into modern orthopedic treatment concepts and reference InGenerons proprietary cell therapy platform, currently under evaluation in ongoing FDA-approved trials.

Summarizing 20 years of both basic and clinical research, the review aims to provide a straightforward look at the current state of orthopedic regenerative cell therapies and clarifies the role of different regenerative cells, such as vaPS cells, in tissue regeneration. The publication highlights the advantages of InGenerons therapeutic approach utilizing ADRCs to develop point-of-care therapies compared to other types of stem cell therapy, including techniques requiring cells to be cultured in a lab. Dr. Eckhard Alt, Director of Stem Cell Research at Tulane University (New Orleans, LA, USA), Executive Chairman of InGeneron and co-author of the paper explains: Using unmodified, uncultured, autologous cells allows for true point-of-care treatment, which can be performed within a short time on the same day in an outpatient facility. Culturing and modifying cells before treatment increases the complexity and cost for patients and physicians and also increases the possibility for contamination of the cells and other health concerns, such as autoimmune rejection, that are not an issue when using ADRCs.

Pointing out another advantage of InGenerons therapeutic approach, Dr. Christoph Schmitz, Head of the Department of Anatomy II at Ludwig-Maximilians University of Munich (Munich, Germany), Advisory Medical Director of InGeneron and co-author of the paper adds, We realized early on that stem cells were important but that they benefitted from other cells contained in ADRCs such as progenitor cells, pericytes, endothelial cells and fibroblasts, which we collect from patients adipose tissue along with their stem cells. All of these cell types play an essential role in tissue regeneration and work synergistically, each affecting the other to promote healing in specific ways that we are still working to fully understand. Therapies that isolate stem cells for culturing in the lab lack these other cell types.

The publication concludes that utilizing ADRCs offers the most attractive therapeutic approach for providing safe and effective treatments, which can be integrated into the modern orthopedic clinical paradigm.

Building on the insights obtained from years of research studying regenerative cells, InGeneron is currently conducting three actively enrolling FDA-approved clinical trials to evaluate its cell therapy platform for the treatment of musculoskeletal indications such as partial-thickness rotator cuff tear, wrist osteoarthritis, and facet joint syndrome.

Publication Details

DOI: https://doi.org/10.1186/s13018-022-02918-8

Citation: Furia, J.P., Lundeen, M.A., Hurd, J.L. et al. Why and how to use the body's own stem cells for regeneration in musculoskeletal disorders: a primer. J Orthop Surg Res 17, 36 (2022).

About the Transpose RT System and Current Clinical Trials

InGenerons Transpose RT cell therapy platform consists of a processing unit, a set of disposables, and Matrase, a proprietary enzyme mixture. The platform allows the isolation of regenerative cells from the patients' own adipose tissue at point-of-care in less than 90 minutes for same-day treatment. The cells are re-administered into the patients damaged tissue by injection under ultrasound or fluoroscopic guidance.

The Transpose RT System is being investigated in several FDA-approved clinical trials and is currently available in the U.S. for research use only. More information on InGenerons actively enrolling clinical trials can be found at http://www.clinicaltrials.gov under the identifiers NCT03752827, NCT03513731, and NCT03503305.

About InGeneron

InGeneron is a clinical-stage biotechnology company developing novel, safe, and evidence-based cell therapies. We are setting new therapeutic standards by enabling minimally invasive treatments that unlock the healing potential of each patients own regenerative cells processed at the point of care for same-day treatment. We currently focus on helping patients impacted by orthopedic conditions and are conducting several clinical trials to validate our technology as a disease-modifying treatment. Based on more than 20 years of research, InGeneron is dedicated to developing therapies supported by clinical evidence and approved by the FDA.

http://www.ingeneron.com

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InGeneron Publishes Overview on Current State and Potential of Regenerative Cell Therapy in Orthopedics - Business Wire

Global Cell Therapy Manufacturing Market, By Therapy (T-Cell Therapies, Dendritic Cell Therapies, Tumor Cell Therapies, Stem Cell Therapies), By Source of Cell (Autologous v/s Allogenic), By Scale of Operation (Preclinical, Clinical, Commercial), By Source (In-House v/s Contract Manufacturing), By Application (Oncology, Cardiovascular Diseases, Orthopedic Diseases, Others), By End User (Pharmaceutical & Biotechnology Companies, Academic & Research Institutes, Others), By Region, Competition Forecast and Opportunities, 2026

New York, Jan. 26, 2022 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Cell Therapy Manufacturing Market, By Therapy, By Source of Cell, By Scale of Operation, By Source, By Application, By End User, By Region, Competition Forecast and Opportunities, 2026" - https://www.reportlinker.com/p06131077/?utm_source=GNW

Global cell therapy manufacturing market was valued at USD3123.44 million in the year 2020 and is anticipated to grow with a CAGR value of 12.0% in the forecast period, 2022-2026 to reach market value of USD6015.09 million by 2026F. The market growth can be attributed to advancing biopharmaceutical industries across the globe. Moreover, increasing dependency on cell therapy and thus therapeutics & pharmaceutical products for the efficient treatment of the patients suffering from critical diseases and conditions is also supporting the growth of the global cell therapy manufacturing market in the next five years. Additionally, growing prevalence of chronic diseases like cardiovascular diseases, cancer disease, along with lifestyle diseases like obesity, diabetes that further deteriorates immunity of the humans further contributes to the growth of the global cell therapy manufacturing market in the future five years. Recent instance of COVID-19 outbreak that caused millions of deaths worldwide has created a demand for advanced cell therapy manufacturing to devise pharmaceuticals, vaccines, etc. Significant development and advancement in cell-based therapies for skin rejuvenation and tendon regeneration are further driving the growth of the global cell therapy manufacturing market in the forecast period.The global cell therapy manufacturing market is segmented by therapy, source of cell, scale of operation, source, application, end user, company, and regional distribution.Based on application, the market is further divided into oncology, cardiovascular diseases, orthopedic diseases, and others.

Oncology sub-segment is anticipated to hold more than 50% of the revenue shares of the market and dominate the application based market segmentation in the upcoming five years.The growth can be attributed to increasing instances of various types of cancer in the global population.

Moreover, increased technological advancement and consistent cell therapy based research for the treatment of cancer is further anticipated to support the market growth.Novartis AG, F. Hoffmann-La Roche AG, Gilead Sciences, Inc., Thermo Fischer Scientific, Inc., Catalent, Inc., JSR Life Sciences LLC (KBI Biopharma Inc), Waisman Center (Waisman Biomanufacturing), Cell and Gene Therapy Catapult, Merck KGaA, Lonza Group, Oxford Biomedica Plc, WuXi AppTec, Charles River Laboratoires International Inc., Institut Merieux (ABL Inc.), BioCentriq, Centre for Commercialization of Regenerative Medicine (CCRM), Fujifilm Holdings Corporation (Fujifilm Cellular Dynamics), Amgen Inc., Bluebird Bio Inc., Takeda Pharmaceutical Company Limited are among the major market players in the global platform that lead the market growth of the global cell therapy manufacturing market.

Years considered for this report:

Historical Years: 2016-2019Base Year: 2020Estimated Year: 2021Forecast Period: 20222026

Objective of the Study:

To analyze and estimate the market size of global cell therapy manufacturing market from 2016 to 2020. To estimate and forecast the market size of global cell therapy manufacturing market from 2021 to 2026 and growth rate until 2026. To classify and forecast global cell therapy manufacturing market based on therapy, source of cell, scale of operation, source, application, end user, company, and regional distribution. To identify dominant region or segment in the global cell therapy manufacturing market. To identify drivers and challenges for global cell therapy manufacturing market. To examine competitive developments such as expansions, mergers & acquisitions, etc., in global cell therapy manufacturing market. To identify and analyze the profile of leading players operating in global cell therapy manufacturing market. To identify key sustainable strategies adopted by market players in global cell therapy manufacturing market.The analyst performed both primary as well as exhaustive secondary research for this study.Initially, the analyst sourced a list of companies the globe.

Subsequently, the analyst conducted primary research surveys with the identified companies.While interviewing, the respondents were also enquired about their competitors.

Through this technique, the analyst could include the companies which could not be identified due to the limitations of secondary research. The analyst examined the companies, distribution channels and presence of all major players across the globe.The analyst calculated the market size of global cell therapy manufacturing market using a bottom-up approach, wherein data for various end-user segments was recorded and forecast for the future years. The analyst sourced these values from the industry experts and company representatives and externally validated through analyzing historical data of these applications for getting an appropriate, overall market size.

Various secondary sources such as company websites, news articles, press releases, company annual reports, investor presentations and financial reports were also studied by the analyst.

Key Target Audience:

Companies, and other stakeholders Government bodies such as regulating authorities and policy makers Organizations, forums and alliances related to cell therapy manufacturing Market research and consulting firmsThe study is useful in providing answers to several critical questions that are important for the industry stakeholders such as manufacturers, suppliers, partners, end users, etc., besides allowing them in strategizing investments and capitalizing on market opportunities.

Report Scope:

In this report, global cell therapy manufacturing market has been segmented into following categories, in addition to the industry trends which have also been detailed below: Global Cell Therapy Manufacturing Market, By Therapy:o T-Cell Therapieso Dendritic Cell Therapieso Tumor Cell Therapieso Stem Cell Therapies Global Cell Therapy Manufacturing Market, By Source of Cell:o Autologouso Allogenic Global Cell Therapy Manufacturing Market, By Scale of Operation:o Preclinicalo Clinicalo Commercial Global Cell Therapy Manufacturing Market, By Source:o In-Houseo Contract Manufacturing Global Cell Therapy Manufacturing Market, By Application:o Oncologyo Cardiovascular Diseaseso Orthopedic Diseaseso Others Global Cell Therapy Manufacturing Market, By End User:o Pharmaceutical & Biotechnology Companieso Academic & Research Instituteso Others Global Cell Therapy Manufacturing Market, By Region:o North AmericaUnited StatesCanadaMexicoo EuropeGermanyFranceUnited KingdomSpainItalyo Asia-PacificChinaJapanSouth KoreaAustraliaIndiao South AmericaBrazilArgentinaColombiao Middle East & AfricaIsraelSouth AfricaSaudi ArabiaUAE

Competitive Landscape

Company Profiles: Detailed analysis of the major companies present in global cell therapy manufacturing market.

Available Customizations:

With the given market data, we offers customizations according to a companys specific needs. The following customization options are available for the report:

Company Information

Detailed analysis and profiling of additional market players (up to five).Read the full report: https://www.reportlinker.com/p06131077/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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Global Cell Therapy Manufacturing Market, By Therapy, By Source of Cell, By Scale of Operation, By Source, By Application, By End User, By Region,...

Avra, Inc.

Ann Shippy, MD

Dr. Charles A. Pereyra

ATLANTA, Jan. 27, 2022 (GLOBE NEWSWIRE) -- via NewMediaWire -- Avra, Inc. (OTC PINK: AVRN), operating as Springs Rejuvenation, (Spring), a Chamblee, Georgia based anti-aging and stem cell center focusing on stem cell therapy, today announced a partnership with Austin TX clinic to expand its operations.

Springs Rejuvenation is excited to announce its new partnership with Ann Shippy MD. A former IBM engineer, Ann Shippy, MD transitioned to the world of medicine in part, in search of better solutions to her own health ailments, which she hadnt found in traditional medicine. Her practice, which is based in Austin, Texas, takes a functional approach to a wide range of health concerns where she has spent more than a decade successfully treating conditions ranging from near-fatal toxicity, neurological disorders, to autoimmunity, infertility and beyond.

Dr. Pereyra, founder of Springs Rejuvenation, stated, She is one of the most intelligent and compassionate humans Ive ever known. When we first met I knew we had a special connection and were both excited about exploring the unknown and pushing to new horizons. I couldnt have made a better friend or partner. We will begin offering treatments immediately.

Dr. Shippy is board-certified in internal medicine and certified in functional medicine, authoring two health manuals, appearing as a guest speaker on numerous platforms, and has founded two health-based foundations. Gaining notoriety for her unique blend of measured, precise data with a heartfelt and sympathetic attitude towards her patients. Whether at a live event, webinar, mastermind presentation or private engagement, Dr. Shippy has always been excited to share with her community the most cutting edge guidance in epigenetic, detoxification, Functional Medicine, and optimal healing.

About Springs Rejuvenation Inc.

At Springs Rejuvenation we strive to be at the cutting edge of regenerative medicine and anti-aging research. Our mission is to provide patients with individualized, state-of-the-art treatment, returning each patient to their natural mobility as quickly as possible.

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With the goal of addressing the root cause of your pain, rather than just masking it. We want to help you achieve whole body health and rejuvenation. This which will help you feel stronger, improve mood, look younger, heal faster and perform at the optimal level. Our patients have found both freedom from pain and improved quality of life.

Our professional staff is uniquely composed of physicians/researchers in the Stem Cell, Anti-Aging research and regenerative medicine, also including sports-related injuries and chronic joint pain.

Our Medical Director & Founder Dr. Charles A. Pereyra is the founder of Springs Rejuvenation Stem Cell Therapy in Atlanta, GA (since 2018). He is our current lead clinical Physician and an expert in Stem Cell, Anti-Aging research and Regenerative medicine. Dr. Juan Pablo Nieto specializes in sports-related injuries as well as chronic joint pain. He has expertise experience with diagnostic ultrasound exams as well as joint and tendon injections with PRP, & prolotherapy. His highlights include caring/treating professional athletes: NBA Wizards & D1 level athletes from different multiple sports and presented research at national conferences.

FORWARD-LOOKING STATEMENTS:

This press release contains forward-looking statements as defined within Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These statements relate to future events, including our ability to raise capital, or to our future financial performance, and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance, or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. You should not place undue reliance on forward-looking statements since they involve known and unknown risks, uncertainties and other factors which are, in some cases, beyond our control and which could, and likely will, materially affect actual results, levels of activity, performance or achievements. Any forward-looking statement reflects our current views with respect to future events and is subject to these and other risks, uncertainties and assumptions relating to our operations, results of operations, growth strategy and liquidity. We assume no obligation to publicly update or revise these forward-looking statements for any reason, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future.

For a discussion of these risks and uncertainties, please see our filings with the OTC Markets Group Inc. Our public filings with the OTC Markets Group Inc are available from commercial document retrieval services and at the website maintained by the OTC Markets at https://www.otcmarkets.com/stock/AVRN/disclosure

Company website(s): http://www.avrabiz.com ; https://springsrejuvenation.com

Company Twitter: @SpringsRejuven1

Email: avrabiz21@gmail.com

Phone: 678-387-3515

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Springs Rejuvenation Partners with Ann Shippy, MD to Offer Treatments in Austin, TX - Yahoo Finance