Groundbreaking Trial Shows Umbilical-Cord Derived Mesenchymal Stem Cell Infusions Save Lives of Sickest COVID-19 Patients – HospiMedica

Image: Camillo Ricordi, M.D., director of the Diabetes Research Institute (DRI) and Cell Transplant Center at the University of Miami Miller School of Medicine (Photo courtesy of University of Miami Health System)

Researchers at the University of Miami Miller School of Medicine (Miami, FL, USA) who led the study believe that treating COVID-19 with mesenchymal stem cells makes sense. Mesenchymal cells not only help correct immune and inflammatory responses that go awry, they also have antimicrobial activity and have been shown to promote tissue regeneration. When given intravenously, mesenchymal stem cells migrate naturally to the lungs. Thats where therapy is needed in COVID-19 patients with acute respiratory distress syndrome, a dangerous complication associated with severe inflammation and fluid buildup in the lungs.

In the new study, 24 hospitalized COVID-19 patients who had developed severe acute respiratory distress syndrome each received two infusions given days apart of either mesenchymal stem cells or a placebo. Researchers found the treatment was safe, with no infusion-related serious adverse events. Patient survival at one month was 91% in the stem cell treated group versus 42% in the control group. Among patients younger than 85 years old, 100% of those treated with mesenchymal stem cells survived at one month.

The researchers also found that recovery was faster among those in the treatment arm. More than half of patients treated with mesenchymal stem cell infusions recovered and went home from the hospital within two weeks after the last treatment. More than 80% of the treatment group recovered by day 30, versus less than 37% in the control group. The next step is to study use of the stem cells in COVID-19 patients who have not yet become severely ill but are at risk of having to be intubated, to determine if the infusions prevent disease progression.

The umbilical cord contains progenitor stem cells, or mesenchymal stem cells, that can be expanded and provide therapeutic doses for over 10,000 patients from a single umbilical cord, said the studys senior author, Camillo Ricordi, M.D., director of the Diabetes Research Institute (DRI) and Cell Transplant Center at the University of Miami Miller School of Medicine. Its a unique resource of cells that are under investigation for their possible use in cell therapy applications, anytime you have to modulate immune response or inflammatory response.

Our results confirm the powerful anti-inflammatory, immunomodulatory effect of UC-MSC (umbilical-cord derived mesenchymal stem cells). These cells have clearly inhibited the cytokine storm, a hallmark of severe COVID-19, said Giacomo Lanzoni, Ph.D., lead author of the paper and assistant research professor at the Diabetes Research Institute. The results are critically important not only for COVID-19 but also for other diseases characterized by aberrant and hyperinflammatory immune responses, such as autoimmune type 1 diabetes.

Related Links:University of Miami Miller School of Medicine

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Groundbreaking Trial Shows Umbilical-Cord Derived Mesenchymal Stem Cell Infusions Save Lives of Sickest COVID-19 Patients - HospiMedica

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Bone Therapeutics, Rigenerand Ink Cell Therapy Deal – Contract Pharma

Bone Therapeutics, a cell therapy company addressing unmet medical needs in orthopedics and other diseases, and Rigenerand SRL, a biotech company that both develops and manufactures medicinal products for cell therapy applications, primarily for regenerative medicine and oncology, have signed an agreement for a process development partnership.Allogeneic mesenchymal stem cell (MSC) therapies are currently being developed at a fast pace and are evaluated in numerous clinical studies covering diverse therapeutic areas such as bone and cartilage conditions, liver, cardiovascular and autoimmune diseases in which MSCs could have a significant positive effect.Advances in process development to scale up these therapies could have major impacts for both their approval and commercial viability. This will be essential to bring these therapies to market to benefit patients as quickly as possible, said Miguel Forte, chief executive officer, Bone Therapeutics. While Bone Therapeutics is driving on its existing clinical development programs, we have signed a first formal agreement with Rigenerand as a fellow MSC-based organization. This will result in both companies sharing extensive expertise in the process development and manufacturing of MSCs and cell and gene therapy medicinal products. Bone Therapeutics also selected Rigenerand to partner with for their additional experience with wider process development of advanced therapy medicinal products (ATMPs), including the conditioning and editing of MSCs.The scope of collaborations between Bone Therapeutics and Rigenerand aims to focus on different aspects of product and process development for Bone Therapeutics expanding therapeutic portfolio. Rigenerand will contribute to improving the processes involved in the development and manufacture of Bone Therapeutics MSC based allogeneic differentiated cell therapy products as they advance towards patients. The first collaboration between the two organizations will initially focus on augmented professional bone-forming cellscells that are differentiated and programmed for a specific task. There is also potential for Bone Therapeutics to broaden its therapeutic targets and explore new mechanisms of action with potential gene modifications for its therapeutic portfolio.In addition to Rigenerands MSC expertise, Bone Therapeutics also selected Rigenerand as a partner for Rigenerands GMP manufacturing facility. This facility, situated in Modena, Italy, has been designed to host a number of types of development processes for ATMPs. These include somatic, tissue engineered and gene therapy processes. These multiple areas of Rigenerand capabilities enable critical development of new processes and implementation of the gene modification of existing processes. In addition, Rigenerand has built considerable experience in cGMP manufacturing of MSC-based medicinal products, including those that are genetically modified.Process development and manufacturing is a key part of the development for ATMPs internationally. Navigating these therapies through the clinical development phase and into the market requires a carefully considered process development pathway, said Massimo Dominici, scientific founder, Rigenerand, professor of medical oncology, and former president of the International Society for Cell & Gene Therapy (ISCT). This pathway needs to be flexible, as both the market and materials of these therapies continues to evolve alongside an improved clinical efficacy.Giorgio Mari, chief executive officer, Rigenerand, said, Rigenerand will offer considerable input from its experience of MSC-based therapies to enable Bone Therapeutics to keep and further accelerate the pace in development of the product processes of its MSC based allogeneic differentiated cell therapy as they advance towards patients. We will continue to use our MSC expertise in the development of Rigenerands own products, as well as in process development and manufacturing cell and gene therapies for partner organizations across the globe.

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Bone Therapeutics, Rigenerand Ink Cell Therapy Deal - Contract Pharma

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Human Mesenchymal Stem Cells Market Can Industry Giants Take Advantage Of This Surrealt Situation?: PromoCell, ThermoFisher, KURABO, Lifeline Cell…

Worldwide Market Reports published a Business research report on Human Mesenchymal Stem Cells Market: Global Industry Analysis, Size, Share, Growth, Trends, and Forecasts 20212026. Human Mesenchymal Stem Cells Market with 100+ market data Tables, Pie Chat, Graphs & Figures spread through Pages detailed analysis gathered modern floats and requests identified with the administrations and items.

The insightful data offered in the report makes it an invaluable resource for industry executives, marketing, sales and product managers, consultants, analysts, and stakeholders that are in search of major industry information in ready-to-access documents with clearly presented tables and graphs.

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This qualitative and quantitative analysis will contain key product offerings, crucial differentiators, revenue share, market size, market status, and strategies of top leading players. The report will additionally cover key agreements, associations, and global partnerships soon to change the dynamics of the market on a global scale.

TheHuman Mesenchymal Stem Cells market report offers clear-cut information about the key business giants Market: PromoCell, ThermoFisher, KURABO, Lifeline Cell Technology, Merck

Global Human Mesenchymal Stem Cells Market: Segment Analysis

The market has various segments such as applications, end-users, and products. These help in determining the growth of a particular segment of a market. The readers can assess why a certain segment is performing better than the other and then make strategic investments. The type segment includes sales value for the forecast period of2012 to 2026. The application segment includes sales by volume and consumption for the forecast period of2012to 2026.

Market Attributes


The market size value in2021

USDXX Million

The revenue forecast in 2026

USDXX Million

Growth Rate

CAGR of XX % from2021 to 2026

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Revenue Forecast, Company Ranking, Competitive Landscape, Growth Factors, And Trends

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U.S., Canada, Mexico, U.K., Germany, France, Italy, China, India, Japan, Brazil, Argentina, Saudi Arabia, South Africa

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Industrial Impact of Covid-19 on Human Mesenchymal Stem Cells Industry:

The outbreak of the pandemicCOVID-19changed the market scenario on the global platform. Many of the regions are facing the biggest economic crisis owing to the lockdowns that were implemented due to the outspread of the coronavirus infection. As the only solution that has been found to contracting this disease is social distancing many countries have implemented strong regulations in regards to people gatherings. Owing to this many of the businesses are working with only 30% of their employees thus not able to bring the maximum production.

Thiscan affect the global economy in 3 main ways: by directly affecting production and demand, by creating supply chain and market disturbance, and by its financial impact on firms and financial markets.

Key Highlights of the Report:

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The in-depth market analysis by some of the most vastly experienced analysts provide our diverse range of clients from across all industries with vital decision making insights to plan and align their market strategies in line with current market trends. Worldwide Market Reports well-researched inputs that encompass domains ranging from IT to healthcare enable our prized clients to capitalize upon key growth opportunities and shield against credible threats prevalent in the market in the current scenario and those expected in the near future.

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Human Mesenchymal Stem Cells Market Can Industry Giants Take Advantage Of This Surrealt Situation?: PromoCell, ThermoFisher, KURABO, Lifeline Cell...

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Beyond laminitis: The potential of regenerative medicine to deliver better outcomes – Horsetalk

An illustration of the equine musculoskeletal diseases discussed in the just-published review and the harvest sites for bone marrow (from the sternum), adipose tissue (from the tail head) and blood (from the jugular vein) for mesenchymal stem cell (MSC) isolation, respectively, for platelet-rich plasma (PRP) and autologous conditioned serum (ACS) preparation. Image:

More studies using regenerative medicine in a bid to improve the welfare of laminitic horses can be expected, according to the authors of a just-published review.

Regenerative therapies in the field of laminitis have gained more interest in recent years, Iris Ribitsch, Gil Lola Oreff, and Florien Jenner noted in their paper in the open-access journal Animals.

The common and painful hoof condition can occur due to any number of systemic or local insults, in either an acute or chronic form. The prognosis depends on the initiating cause and is generally favourable to poor.

Current treatment options are mainly limited to pain management, cryotherapy, hoof support, and, depending on the cause, treatment of the underlying disease.

Since no curative treatment is available, high hopes are pinned on new regenerative treatment strategies, the trio, from the University of Veterinary Medicine Vienna, noted in their review exploring the use of regenerative medicine for equine musculoskeletal diseases.

They described the use of mesenchymal stem cells (MSCs) in one study in an attempt to regulate the severity of the inflammatory response in the hoof.

Nine horses with chronic laminitis were injected three times with MSCs suspended in platelet-rich plasma through the palmar digital veins.

All horses in the study had been treated previously with conventional laminitis treatments without much success. MSCs derived from the patient, as well as other horses, were used without any complications.

In the long term, a significant improvement could be noted in vascularity, structure, and function of the hoof.

The review team noted that the distribution of MSCs injected into the lower limb might be improved by using different injection methods, such as into an artery rather than into a vein, potentially improving the therapeutic benefit.

Platelet-rich plasma, which contains high levels of growth factors and anti-inflammatory factors, can aid in regulating inflammation, decreasing pain and assist with the development of new blood vessels.

Due to those abilities, it has also been proposed as a therapeutic option for chronic laminitis.

Although the literature reporting treatment of laminitis with platelet-rich plasma is limited to case reports, the results are encouraging, Ribitsch and her colleagues noted.

Chronic laminitis patients reportedly showed improvement in comfort and hoof conformation after injection of platelet-rich plasma through the coronary band.

The trio noted that lameness caused by musculoskeletal disease is the most common diagnosis in equine veterinary practice.

Many of these orthopaedic disorders are chronic problems, for which no clinically satisfactory treatment exists.

Thus, there are high hopes for regenerative medicine, which aims to replace or regenerate cells, tissues, or organs to restore or establish normal function.

They noted that some regenerative medicine therapies have already made their way into equine clinical practice with promising but diverse results, mainly to treat tendon and cartilage problems, and degenerative joint disorders.

In equine practice, several regenerative therapies, such as MSCs, platelet-rich plasma, autologous conditioned serum and autologous protein solution, have been used for various musculoskeletal problems over the last decade.

However, the field of regenerative medicine still has to live up to high hopes and expectations placed on it, both from a medical and financial viewpoint.

The authors noted that large placebo-controlled studies are still scarce despite promising results from multiple experimental and preclinical studies, case reports and small randomised and controlled studies.

Regenerative medicine also faces several challenges, such as the lack of well-defined cells to be used as therapeutics and insufficient understanding of their mode of action. Some mechanisms involved, such as the interplay of growth factors, cytokines, proteinases, and cellular mediators, remain poorly understood.

To exploit the full potential of tissues to heal, our understanding of how reparative processes are mediated and may be directed towards regeneration rather than scarring repair needs to be improved.

The field of equine regenerative medicine involves much pioneering work, they noted, with variable treatment protocols using different routes of administration and/or dosages of cells, which may contribute to the discrepancies between promising experimental results and clinical effectiveness.

Hence, intensive research efforts are still ongoing and required to find ways to exploit the maximal potential of regenerative medicine.

The authors traversed the current knowledge around MSCs, autologous blood products and the various applications of regenerative therapies.

They noted that most of the applied regenerative therapies are still at an experimental state and patients are treated within the scope of clinical trials.

Looking to the future, they noted that models of tissue injury and naturally occurring regeneration have shown the importance of the immune response for tissue repair, highlighting the necessity to regulate inflammatory processes to aid regeneration.

Traditional regenerative medicine focused on transplanting exogenously prepared cells or tissue while neglecting to consider the inflammatory and degenerative microenvironment.

Novel approaches try to work with, not against biology, to create an environment to induce regeneration within the horse.

To this end the genetic elements, regulatory pathways and specific cell populations that limit or allow intrinsic regeneration need to be identified to be able to use mammalian tissue development and regeneration as a blueprint to guide the development of novel regenerative therapies.

Ribitsch, I.; Oreff, G.L.; Jenner, F. Regenerative Medicine for Equine Musculoskeletal Diseases. Animals 2021, 11, 234.

The review, published under a Creative Commons License, can be read here.

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Beyond laminitis: The potential of regenerative medicine to deliver better outcomes - Horsetalk

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[Full text] Osteonecrosis of the Jaw Beyond Bisphosphonates: Are There Any Unknown | CCIDE – Dove Medical Press


Recent literature reviews suggest that bisphosphonates (BPs) may contribute to the growing number of cases of osteonecrosis involving the maxilla and mandible that are associated with the pathogenesis of BP-related osteonecrosis of the jaw (BRONJ).1 In the discussion concerning BRONJ, a distinction must be made between diseases featuring reduced osseous mineral content, which may be counteracted by BPs (such as those occurring during menopause or in cases of osteoporosis), and cases that present with indications for BPs (such as tumors). BPs have been used in the treatment of multiple myeloma, breast cancer, prostate cancer, and other tumors. In patients with metastatic breast cancer, the bones are affected in around two-thirds of cases. To protect patients from bone fractures and to reduce pain, patients are often prescribed BPs or a special antibody that prevents the breakdown of, and subsequently stabilizes, affected bone. BRONJ is a newly emerging problem that is recognized as a serious complication of BP therapy, primarily following intravenous (IV) administration.2

The concern is that BPs affect the natural remodeling of bone tissues and delay the breakdown of older bone structures. BPs are potent inhibitors of bone resorption and have a chronic effect over a half-life of at least 5 years, possibly exerting their effects for more than 10 years. BRONJ is a seemingly growing epidemic associated with osteonecrosis of the jawbone (ONJ).35 The long-term effects of oncological-related BP treatment on alveolar bone quality include the impact on BP-induced overexpression of alveolar bone remodeling. There are increased osteosclerotic properties in the alveolar bone that are associated with significantly greater bone volume and higher bone density.6,7 The risk of BP therapy is divided into two categories: local and systemic risk factors; thus, a distinction must be made between oral and IV administration. Local oral risk factors for BRONJ in cancer patients include dentoalveolar surgery, dental extraction, and dental implant insertion.8 Periodontal infections also significantly increase the risk of BRONJ in cancer patients.9 In addition, there is a significant correlation between the use of removable prostheses, the administration of high-dose IV BPs, and an increased risk of BRONJ.10 In patients receiving oral BP therapy for the treatment of osteoporosis, the prevalence of BRONJ only increased 0.21% from close to 0%. Systemically, however, there is a much higher risk associated with the IV injection of BPs. This is closely related to the frequent use of BPs in cancer patients who receive a significantly higher total dose over a longer duration.11 The mean and minimum time for the development of ONJ is 1.8 years and 10 months, respectively.12 The risk of BRONJ in cancer patients exposed to BP therapy is from 50100 times higher than in cancer patients treated with a placebo. The BRONJ risk for the RANKL inhibitor denosumab was between 0.7% and 1.9%.13,14 The risk of ONJ in cancer patients treated with high doses of IV BPs appears to be significantly higher: in the range of 110 per 100 patients (depending on therapy duration).15 A recent review reported a wide-ranging BRONJ incidence of 027.5% that was associated with the IV administration of BPs, with an average incidence of 7%.16 The cumulative frequency varied from 0.812.0% and was estimated to be up to 30.0% in some reports.17,18 Despite numerous publications on the subject, the overall pathogenesis of BRONJ does not yet appear to be fully understood. In particular, the reasons why only a subset of patients (<30%) receiving IV BPs develop BRONJ remain unclear. Although most patients that develop BRONJ have a history of tooth extraction or injury, these factors do not fully explain the occurrence of BRONJ.8 The development of BRONJ in edentulous areas in patients with no apparent history of injury suggests that pre-existing conditions, such as subclinical infections or potentially necrotic areas of the jawbone, may contribute to the conditions that lead to the development of BRONJ.

Why does BRONJ develop in up to 30% of individuals following IV BP therapy and not the remaining 70%? This review raises the question of whether little-known or difficult-to-identify, pre-existing, impaired bone remodeling, such as that occurring in aseptic-ischemic osteonecrosis of the jaw (AIOJ), bone marrow defects (BMD), or fatty-degenerative osteonecrosis of the jawbone (FDOJ), represents a local risk factor in the development of BRONJ.

There is still a limited scientific understanding of the relationship between ONJ and BPs.19 In order to clarify the research question and present the background and specific common characteristics of AIOJ/BMD/FDOJ and BRONJ, an extensive literature search was carried out in PubMed Central. In the literature, the terms aseptic-ischemic osteonecrosis of the jaw (AIOJ), bone marrow defects (BMD), and fatty-degenerative osteonecrosis of the jawbone (FDOJ) are used to describe an intramedullary phenomenon with the same pathogenesis, morphology, and pathohistology.

The American Association of Oral and Maxillofacial Surgeons published four staging criteria (at risk, Stage 03).20 Stage 0 is of particular interest in our research as it refers to patients with no clinical evidence of exposed bone, but presence of non-specific symptoms or clinical and/or radiographic abnormalities. The discussion concerning BRONJ is complicated by the fact that there are two clinical forms of BRONJ. The first presents as exposed bone in the maxillofacial region with clinically recognizable necrotic bone that is visibly exposed through the oral mucosa or facial skin, and present for more than 8 weeks, which is referred to as so-called exposed BRONJ.15 The second form of BRONJ is particularly interesting for our investigation; it was recently emphasized that BRONJ does not always appear with necrotic bone visible through a breech in the oral mucosa.21 This form is referred to as non-exposed BRONJ (NE-BRONJ). In the absence of exposed bone, it is characterized by clinical features associated with the jaw, such as unexplained jawbone pain, fistulas/sinus tracts, loose teeth, and swelling.22,23 Diagnosing NE-BRONJ is difficult, as other common jawbone diseases, such as odontogenic infections, may cause similar symptoms and must be excluded. The non-exposed variant may comprise up to one third of all BRONJ cases and is thus not uncommon;24 however, this previously underestimated NE-BRONJ is difficult to accurately diagnose. Recently published papers emphasize that NE-BRONJ has received little attention so far and does not fulfill the current definition of BRONJ.25 Nevertheless, NE-BRONJ belongs to the same disease as exposed BRONJ and should be identified as part of the full spectrum of BRONJ (see the section titled, Case descriptions of AIOJ/BMD/FDOJ, non-exposed BRONJ, and Actinomyces colonization).26

Our investigation requires the identification of the basic immune mechanisms associated with BP administration. Specifically, which mechanism is behind the anti-tumor activity of BPs in cancer patients?

Various studies postulate that BPs change the bone microenvironment around cancer cells, which may prevent cancer cell survival and disease recurrence.27 BPs may also reduce the appearance of disseminated tumor cells. The formation of metastases is complex; mesenchymal stem cells (MSCs) are predominantly found in the bone marrow.28 MSCs may contribute to the formation of metastases through various mechanisms: (1) MSCs are recruited to develop breast tumors where they can enhance the metastatic potential of weakly tumorigenic breast cancer cells;29 (2) MSCs and other bone marrow cells may form a pre-metastatic niche within the specific tissues to which tumor cells metastasize;30 and (3) MSCs are able to maintain the growth and survival of cancer cells in the bone microenvironment where they may contribute to the formation of niches for dormant micrometastases that can later form distant metastases. BPs significantly reduce the ability of MSCs to migrate, thereby reducing the growth and survival of cancer cells.31 Thus, the effects of BPs on MSCs in the bone marrow microenvironment contribute to anti-tumor activity by affecting the ability of MSCs to migrate and develop tumors in pre-metastatic niches. BPs disrupt the interaction between MSCs and breast cancer cells within the bone microenvironment, where BPs may also directly inhibit breast cancer cell growth.

The antiangiogenic effect of BP administration in tumor patients also plays a role in therapy.32 When administered systemically, BPs effectively inhibit angiogenesis. The pronounced antiangiogenic properties of BPs enhance their effectiveness in the treatment of malignant bone diseases. In addition to suppressing RANTES/CCL5 (R/C) expression in MSCs, BP administration plays a role in the treatment of tumor patients.33 Similar to exogenous glucocorticoids and estrogen,34 BPs are ischemic and hypoxia-related stressors of bone health that alter jawbone metabolism, thus leading to osteonecrosis. While tumor-associated BP therapy is currently the heavy weight for bone health, it may accelerate existing, chronic pathophysiological events within the microcirculation of bone marrow compartments in the jaw. BRONJ development is often characterized by a slow start and usually presents with infarcts and thrombosis of small vascular sections of the supplying artery within the medullary canal; these features also correspond to AIOJ/BMD/FDOJ. Myeloid elements (including fat marrow) liquefy and cancellous trabeculae are resorbed, so that individual bone spaces merge and gradually create larger cavities.

If we compare the findings in the sections titled, Bisphosphonates and mesenchymal stem cells and Bisphosphonates and antiangiogenesis to pre-existing AIOJ/BMD/FDOJ, several strikingly common characteristics shared by BRONJ and AIOJ/BMD/FDOJ can be observed that help to answer our research question. In the sections following Bisphosphonates and antitumor therapy, we present the foundations for the development of AIOJ/BMD/FDOJ and draw similarities with the development of BRONJ.

The key function of proinflammatory chemokines R/C in the formation of breast cancer and its metastasis, as well as a possible connection with the intramedullary signaling of R/C overexpression from AIOJ/BMD/FDOJ areas, has been pointed out in previous studies.35,36 The conspicuous overexpression of R/C in little-known BMDs, as found in AIOJ/BMD/FDOJ, has been reported.37,38 R/C overexpression is a regulator of healthy bone metabolism in bone needing repair. The starting point for a typical AIOJ/BMD/FDOJ BMDs is the expression of R/C and its chemokine receptors (CCR5) in both osteoblasts (OBs) and osteoclasts (OCs). Ligands (CCL5) and receptors (CCR5) simultaneously activate autocrine and paracrine mechanisms in the bone.39 One study examined the effects of BPs on human primary OBs and was able to show that the overexpression of proinflammatory R/C from BP-treated OBs also occurs in areas affected by BRONJ.40 The secretion of proinflammatory cytokines interleukin (IL)-8 and R/C increased after 14 days of treatment with the highest dose of BPs.40 The complexity of cytokine control becomes clear at this point. In contrast to the tumor, where BPs in the MSCs reduce R/C expression to such an extent that metastasis is prevented, R/C expression is increased by BPs in OBs. If AIOJ/BMD/FDOJ is already present, it may be assumed that the associated increased R/C secretion is thus further increased by BPs. Specifically, NE-BRONJ may develop as BPs increase the expression of IL-8 and R/C.41 Other researchers have confirmed increases in the secretion of proinflammatory IL-8 and R/C from BP-treated OBs.42 Combined with the lower proliferation rate of OBs and a decrease in their differentiation, higher doses or accumulations of BPs cause undesirable local changes in the bone by increasing the secretion of IL-8 and R/C from OBs. If these findings are applied to BP administration in the context of a chronic, pre-existing AIOJ/BMD/FDOJ area, then such areas may be expected to exhibit increased R/C secretion in response to BPs. This increase may result from the inhibition of OC activity, leading to the development of BRONJ. Figure 1 summarizes the effects of BP administration on the pre-existing physiological derailments associated with tumor and osteoporosis development.

Figure 1 Comparison of the effects of BP administration (+BP) in the context of a tumor (upper part of Figure 1) and pre-existing osteoporosis (lower part of Figure 1). Legend: The red arrows indicate overactivity; the green arrows show reversal following BP administration.

In the literature, the vascular composition of AIOJ/BMD/FDOJ is characterized by the fact that blood flow in the medullary canal is impaired by micro-infarcts, which leads to chronic marrow ischemia.43 BRONJ also shows reduced vascularization in the medullary canal.44 Several publications have shown that ischemic bone diseases such as AIOJ/BMD/FDOJ and BRONJ are of multifactorial origin and emphasize the multiple stroke model as the cause of ischemic bone diseases.45,46 In the orthopedic literature, intensive research conducted on the development of ischemic bone disease in the early stages of the disease process is presented.47 Our aim here is to apply this knowledge not only to extreme forms of the disease, such as osteoradionecrosis and BRONJ, but also to chronic, subclinical, and ischemic forms such as bone marrow edema and AIOJ/BMD/FDOJ, which often progress asymptomatically. Many of these forms are manifestations of both local and systemic risk factors that compromise circulation in the bone marrow, and may also impact on the homeostasis of bone resorption and formation, in addition to BP therapy. The importance of this multifactorial exposure to risk factors for ischemia and the associated causal genetics that are very similar to those in cases of AIOJ/BMD/FDOJ is shown by observing how bone that is exposed to BPs demonstrates minimal OC activity, followed by the deposition of newly formed, thicker bone with reduced vascular supply.48 The resulting mosaic-like pattern of bone remodeling is strikingly similar to that found in Pagets disease, which tends to be associated with the development of osteomyelitis.49 Similar to AIOJ/BMD/FDOJ, the remodeling induced by BPs leaves cavities, otherwise known as cavitations, which leads to both necrosis and unlike that which is found in AIOJ/BMD/FDOJ subsequent infection by colonizing bacteria. Many patients with AIOJ/BMD/FDOJ have inherited prothrombotic tendencies, which is comparable to what is found in patients with idiopathic osteonecrosis of the femoral head (Pagets disease) and includes thrombophilia and hypofibrinolysis.5052 Although a consensus has been reached that ischemic marrow edema is not part of the pathogenesis of BRONJ,53 it is regarded as a typical characteristic of AIOJ/BMD/FDOJ, serving as a precursor to BRONJ development. Systemic antibiotic therapy has limited access to these avascular zones and surgical debridement is usually necessary.

The initial OB situation found in AIOJ/BMD/FDOJ is highly characteristic; under pathological conditions, OBs express R/C chemokines in a non-physiological manner.54,55 The increasing frequency of ONJ and its possible association with high cumulative doses of BPs was investigated in one study, which concluded that high doses of BPs had both OC and OB effects, and thus bone remodeling was inhibited in vivo.56 Other researchers have examined the proliferation, viability, expression, and secretion of bone markers and cytokines/chemokines from primary OBs following exposure to BPs.42 Increased concentrations of proinflammatory cytokines were found in response to BPs. Similarly, increased R/C expression is present in AIOJ/BMD/FDOJ. Following treatment with the highest dose of BPs, the secretions of proinflammatory cytokines IL-8 (P<0.001) and R/C (P<0.001) were significantly increased after 14 days. In addition, the secretion of proinflammatory R/C from OBs exposed to BPs increased. It has also been determined that R/C plays a role in the etiology of the osteolytic changes that are present in AIOJ/BMD/FDOJ.37,57 The aim of another study was to investigate the effect of BPs on human OBs in vitro, while considering RANKL and osteoprotegerin (OPG), both of which mediate OC differentiation.40 OPG increased significantly in the group that received BPs at a dose of 10 M, while RANKL expression decreased significantly with different concentrations of BPs. In summary, exposure to various BP concentrations had a positive effect on OB differentiation, but did not affect proliferation. In contrast, the BP-associated changes in RANKL and OPG production contributed to the suppression of osteoclastic bone resorption. Excess R/C leads to OC inhibition which, in our model, also leads to a disturbance in RANK/RANKL homeostasis (see Figure 2). The chain of reactions that arise from pre-existing AIOJ/BMD/FDOJ and BP administration result in the development of BRONJ in response to the subsequent OB depression; it also leads to increased OC apoptosis. In addition, bone densification takes place following BP administration as a result of increased OB activity. As such, osteonecrosis occurs in the jawbone when BPs are used parenterally. The reasons for these different reactions to BPs have not yet been clarified.

Figure 2 The effects of BP administration and the characteristics of AIOJ/BMD/FDOJ both include depressed alkaline phosphatase (AP) activity with subsequent R/C overexpression. On the one hand, this leads to OC inhibition and, on the other, to RANK/RANKL deactivation, which subsequently causes increased OC apoptosis and depressed OB activity resulting in BRONJ development. Legend: The red arrows indicate deactivation; the green arrows show a reversal of the effect following BP administration.

The first step in tumor necrosis factor alpha (TNF-a)-induced OC genesis occurs in the bone marrow.58 Although mature OCs erode the resorption of the bone as a focal point over the course of months to years, the lifespan of individual OCs is only a few weeks. Thus, mature OCs must be constantly replaced. With respect to OC formation, TNF-a directly stimulates the formation of mature OCs,59,60 and supports and promotes the survival of mature OCs.61 TNF-a increases the survival time of OCs to extend the duration of bone resorption. In the early stages of AIOJ/BMD/FDOJ, the situation for OCs is highly contradictory: the extremely low TNF-a values found in areas of AIOJ/BMD/FDOJ as compared to the values in healthy jawbone samples (as documented in our previous studies) indicate that any inflammatory erosion due to TNF-a supported OC formation is unlikely. Due to reduced TNF-a activation, OC formation in AIOJ/BMD/FDOJ is inhibited, which results in a fatty-degenerative morphology.62

In the same way, BPs inhibit the ability of OCs to resorb bone. They do so by suppressing farnesyl diphosphate synthetase activity, which inhibits OC recruitment and impacts the life expectancy of OCs through increased apoptosis. Where the OC function is excessively inhibited, dying OCs will not be replaced, and the capillary network of the bone will not be maintained, which leads to BRONJ.19 The ability of BPs to regulate bone turnover by suppressing OC activity has led to its widespread use in the treatment of osteoporosis, Pagets disease, humoral hypercalcemia, and in tumors metastasizing to bone.17,63 Several studies have shown the effectiveness of BPs in suppressing OC activity in arthritic bone erosions, which was comparable to the effects of OPG injections.64

The initial alkaline phosphatase (AP) situation in AIOJ/BMD/FDOJ is as follows: AP has an optimum pH in the alkaline range. The pH level of AIOJ/BMD/FDOJ areas, however, is reduced as a consequence of the proinflammatory characteristics of R/C overexpression, resulting in a chronic inflammatory state. AP activity is thus inhibited within the increasingly acidic environment of such areas. Furthermore, BPs increase R/C secretion from OBs, and the acidity of areas affected by AIOJ/BMD/FDOJ, together with an excess of R/C, leads to OC inhibition.65 At the same time, there is also reduced osteogenesis due to the suppression of AP activity,66 as well as the overexpression of R/C that is present in AIOJ/BMD/FDOJ areas and also caused by BP administration. In our model, these two factors led to OC inhibition via disturbed RANK//RANKL homeostasis. In addition, depressed OB activity and increased OC apoptosis result in BRONJ development. While the skeletal bone consolidation that results from BP administration occurs in response to increased OB activity, BRONJ develops in the jawbone when BP is administered parenterally. The reasons for these different responses to BPs have not yet been clarified. If we apply these considerations to an existing AIOJ/BMD/FDOJ area (as shown in Figure 2), then BRONJ and AIOJ/BMD/FDOJ both show suppressed AP activity with subsequent R/C overexpression.67 This leads to OC inhibition and RANK/RANKL deactivation and, subsequently, increased OC apoptosis. Decreased OB activity may ultimately lead to the development of exposed BRONJ.

Despite the similarities detailed in the section titled Osteoimmunological parameters of AIOJ/BMD/FDOJ and BRONJ with the same impact in response to BPs, BRONJ and AIOJ/BMD/FDOJ present two very different clinical pictures; different reactions to BP administration are also likely to occur.

The initial involvement of RANKL in AIOJ/BMD/FDOJ has been described in the literature as follows: pathological increases in levels of R/C and MCP-3 from activated OBs stimulate chemotactic recruitment and RANKL formation of resorptive OCs and aggravate local osteolysis. However, BP administration indirectly inhibits OC maturation by increasing OPG protein secretion and decreases transmembrane RANKL expression in human OBs. Several studies have shown that although BPs do not significantly affect RANKL gene expression, they reduce transmembrane RANKL protein expression in OBs.68,69 This shows that BPs, in addition to directly inhibiting mature OCs, prevent OC recruitment and differentiation by splitting transmembrane RANKL into OBs. OC activation and RANKL activation in areas of AIOJ/BMD/FDOJ, and OC inhibition and RANKL inhibition in BRONJ distinguish these two forms of derailed bone metabolism and thus yield different clinical results. Specifically, imperceptible fatty osteolysis of the marrow structures in AIOJ/BMD/FDOJ and painful BRONJ sequestrum arise as a result. BPs have been shown to downregulate the expression of RANKL, the OC-differentiating factor produced by OBs.70

The initial involvement of OPG in AIOJ/BMD/FDOJ is described in the literature. Since the TNF-a level found in AIOJ/BMD/FDOJ represents only 50% of the TNF-a level in healthy jawbone,36,37 the OPG enzyme that belongs to the TNF family is deactivated. In the resulting osteolysis found in areas of AIOJ/BMD/FDOJ, this leads to reduced RANKL binding and thus results in OC activation. In conclusion, data from previously published studies have suggested that BPs modulate the production of OPG by normal OBs, which may contribute to the inhibition of OC bone resorption.71 As the production of OPG increases with OB maturation, the amplification of OPG by BPs may be linked to OB differentiation via stimulatory BP effects. BPs have been shown to increase the gene expression for the decoy receptor, OPG, in human OBs.71 OPG balance is disturbed in both AIOJ/BMD/FDOJ and BRONJ, albeit in opposite ways. However, the prior imbalance of OPG activity in AIOJ/BMD/FDOJ may increase the effects associated with BP administration.

With respect to the exposed variant of BRONJ, radiographic procedures are required in order to determine the extent to which the degree of ossification has increased.72 However, the existence of this variant of BRONJ is clinically evident. In contrast, the non-exposed BRONJ variant and AIOJ/BMD/FDOJ are associated with very similar problems in terms of diagnostic imaging. As with AIOJ/BMD/FDOJ, the prevalence of this variant of BRONJ is largely underestimated as the disease is often underdiagnosed and under-reported.73 Studies have shown that almost a quarter of patients with BRONJ remain undiagnosed.74

The initial histopathological presentation of AIOJ/BMD/FDOJ found in the literature is as follows: Bouquot describes these bone modeling disorders as ischemic osteonecrosis, which is a bone disease characterized by the degeneration and death of marrow and bone due to a slow or abrupt decrease in marrow blood flow.75 Clumps of coalesced, liquefied fat (oil cysts) may be seen. Bone death is represented by a focal loss of OCs. Dark masses of calcific necrotic detritus may often be present.75 The histopathological features of AIOJ/BMD/FDOJ include necrotic adipocytes and fibrosis, but an almost complete absence of inflammatory cells.76 Additional research has shown the role of aseptic necrosis following injury or drug therapy in the pathophysiology of BRONJ. Aseptic bone necrosis, as found in AIOJ/BMD/FDOJ, has been reported as a manifestation of selected systemic diseases and also documented following operations, trauma, and immunosuppressive therapy at the site of BRONJ.77,78 The development of aseptic necrosis has been documented in the upper and lower jaw, particularly following osteotomies.79,80 Researchers have observed a relationship between oral BP use and non-specific aseptic osteonecrosis among a cohort of older cardiovascular patients.81 Other researchers have identified necrotic liquefaction, which often extend to large areas of the jaw, especially within BRONJ lesions of cancer patients, as shown using digital volume tomography (DVT)/cone beam computed tomography (CBCT).82 Research has been published on BRONJ samples that were characterized by low to moderate inflammation.83 This is in accordance with other reports of histopathological analyses of BRONJ samples.48,78,8486 Bone samples from BRONJ patients were investigated by microscopy and the presence of inflammatory infiltrates in the bone tissues was not observed.87 These studies have demonstrated that aseptic necrosis, a lack of inflammatory reactions, and empty OC lacunae are common histopathological features of AIOJ/BMD/FDOJ and BRONJ.

The diagnostic difficulties associated with BRONJ and AIOJ/BMD/FDOJ present another common feature. In order to diagnose BRONJ with imaging procedures, the Task Force Report of the American Society for Bone and Mineral Research highlights that the differential diagnosis of BRONJ should exclude other common intraoral diseases such as periodontitis, gingivitis, infectious osteomyelitis, osteoradionecrosis, neuralgia-inducing cavitational osteonecrosis (NICO), bone tumors, and metastases.15 The authors of the report thus rule out an etiological equation for diagnosing NICO and BRONJ. The current review is focused on the potential role of imaging techniques in the diagnosis of the early stages of BRONJ. A combination of clinical and radiological symptoms suggest that, while not specific to BRONJ, they may collectively be more comprehensive and representative of the bone disease process.2 The American Association of Maxillofacial Surgery accepts the use of imaging techniques when detecting BRONJ during presurgical evaluation.72 It is important for the BRONJ patient that various imaging methods be examined critically prior to being adopted for the early detection and diagnosis of BRONJ.

Figure 3 Left panel shows jawbone area 18; hematoxylin and eosin staining, magnification 200. The lower half of the image illustrates eosinophilic bone substance with empty osteocyte cavities corresponding to devitalized bone sequestrum. Middle part of the left panel: Highly irregular trabecular surfaces with a wide edging comprised of Actinomyces colonies surrounded by a wall of leukocytes. Upper part of left panel: Fibrin particles and individual lymphocytes. Right panel: Actinomyces granules visualized in a PAS reaction; the red color represents a broad band of granules in the middle. The lower edge of the right panel images once again shows a bone sequestrum and typically empty osteocyte lacunae. Diagnosis: Aseptic bone necrosis with Actinomyces colonization.

The histopathological changes in necrotic bone may be visualized with MRI scans, as with CBCT/DVT. The images detect progressive cell death and the repair response (ie, edema). As the fat cells in normal bone marrow provide high signal intensity, it may be assumed that signal changes evident in the marrow are related to the death of fat cells. Necrotic adipocytes are a morphological characteristic of AIOJ/BMD/FDOJ.76 Following the application of a contrast agent, areas of ischemia may be identified as non-enhancing regions. Cases in which fibrosis and sclerosis of the bone occur may also result in lower signal intensity. Nevertheless, the currently available data on MRI results for BRONJ are limited,96 as are those related to AIOJ/BMD/FDOJ. Studies showed positron-emission tomography (PET) as a sensitive method for diagnosis of BRONJ. Thus, PET could be useful for evaluating the severity of BRONJ.97

2D-OPG is used to identify osteopathies of the jawbone. However, this imaging technique fails to show AIOJ/BMD/FDJ areas, thus generating false-negative findings. As a result, AIOJ/BMD/FDOJ have been highly neglected in dentistry and medicine.98 Therefore, transalveolar ultrasound sonography (TAU) appears to be necessary as an additional imaging technique in order to improve the diagnosis of AIOJ/BMD/FDOJ.99,100 A newly developed TAU device (TAU-n) measures sound velocity attenuation when the bone marrow has been penetrated. An ultrasound transmitter is placed over the jaw area and a thumbnail-sized receiver is placed inside the mouth. To obtain reproducible results when measuring bone density, the transmitter and receiver are arranged in a coplanar and fixed position. The parts of the receiving unit are placed inside a patients mouth, the acoustic coupling between those parts and the alveolar ridge is performed with the aid of a semi-solid gel (Figure 3). With the receiver containing 91 piezoelectric fields, sound waves are registered and converted into a color graph of the corresponding areas of bone density (Figure 4).On the graphic visualization, green indicates healthy, dense, and solid bone, yellow indicates the presence of ischemic metabolism, and orange and red highlight areas of AIOJ/BMD/FDOJ presence.101

Figure 4 Left panel shows positioning of transmitter (outside) and receiver (enoral) in the lower jaw; the red band marks the cheek. Right panel shows the transmitter (in blue at the right) and receiver (in green at the left) in a fixed coplanar position (blue bar connecting the transmitter and receiver); semi-solid gel pads between the transmitter and the cheek on the outside of the mouth and between receiver and the alveolar ridge in the enoral position; trans-alveolar ultrasonic impulse from the transmitter to receiver (arrows in blue).

Figure 5 Inconspicuous 2D-OPG findings (left panel); suspected osteolytic processes in areas 1719 in the sagittal section of the image using DVT (right panel). Lower panel: TAU measurement from region 17 to retromolar region 19. Legend: Green areas indicate normal bone density; yellow, orange, and red areas show decreasing bone density until complete osteolysis is reached.

A clinical case of a 55-year-old patient with prostate carcinoma who was treated with parenteral BPs received an X-ray diagnosis of non-exposed BRONJ with normal intraoral findings in the right upper jawbone from area 17 to retromolar area 19. While 2D-OPG of area 18/19 showed no suspicious findings, the CBCT/DVT image demonstrated ossification irregularities and partial cavities that resembled AIOJ/BMD/FDOJ. The development and progression of BRONJ could not be reliably determined by reference to these images and it was not possible to make a differential diagnosis. In contrast, TAU-n images clearly indicated osteolysis (see Figure 4, below). The postoperative light microscopy findings from area 18/19 showed marrow with adipose tissue, significant fibrillar and myxoid degeneration of adipocytes, individual lymphocytes, and mast cells; however, no florid inflammation was observed. These are the typical histological features of AIOJ/BMD/FDOJ.76 It is worth noting, however, that there was a large bone sequestrum with empty OC cavities, highly irregular trabecular surfaces, and empty marrow spaces, with Actinomyces colonization (Figure 3).

Several reviews have indicated that light microscopy examinations were able to detect that 68.8% of BRONJ cases featured Actinomyces colonization.32 Anaerobic Actinomyces has long been associated with necrotic bone findings in BRONJ lesions.102 Actinomyces colonization is thus a top priority as a possible pathological trigger with respect to BRONJ. Since we have not identified bacterial colonization in areas of AIOJ/BMD/FDOJ in our own studies,103 an accompanying secondary Actinomyces colonization seems to be an additional prerequisite for the development of BRONJ from an area of AIOJ/BMD/FDOJ in response to BP administration.

Table 1 displays all studies and their impact on the research question based on the inclusion and exclusion criteria in literature review.

Table 1 The Table Displays the Criteria for Inclusion of Specific Manuscripts in Our Research. Exclusion Criteria Were Unspecific Reviews Concentrating on Exposed BRONJ Only

Can hitherto little-known, yet according to our clinical experience37,76 epidemiologically widespread AIOJ/BMD/FDOJ represent cofactors in the development of BRONJ? The development of biological processes takes place in different stages and during various phases of transition. This also seems to be the case for BRONJ, as the exposed form found in the maxillofacial region represents the final, late-stage form of the NE-BRONJ variant. The focus of our study is thus on the early stage of BRONJ (Stage 0) without exposed bone, as based on the recommendations of the American Association of Oral and Maxillofacial Surgeons.5,20,104 Our hypothesis considers the NE-BRONJ variant as one stage of development featuring an unrecognized BMD that is characteristic of AIOJ/BMD/FDOJ and amplified by BP administration. The cumulative effects of BPs on pre-existing AIOJ/BMD/FDOJ support this premise. The relationship between AIOJ/BMD/FDOJ and the administration of BPs (as shown in Figure 6) leads, etiologically, to the non-exposed BRONJ variant, which is less clearly described in the literature than the late-stage form of BRONJ, and also results in considerable oral impairment.

Figure 6 Overview of the individual osteoimmunological signal cascades present in AIOJ/BMD/FDOJ and their conversion or amplification following BP administration, resulting in the development of BRONJ. Legend: A pair of arrows, one red and one green, indicates the reinforcement or, in one instance, the reversal of the typical overexpression or inhibition found in AIOJ/BMD/FDOJ following BP administration.

As BPs and AIOJ/BMD/FDOJ exert the same effects, resulting in the hyperfunctioning of R/C expression, OB activity, hypoxia/ischemia, and the inhibition of OC activity, vascularization, and AP activity, AIOJ/BMD/FDOJ may be regarded as a prerequisite to the formation of BRONJ. Changes in silent AIOJ/BMD/FDOJ processes, including strongly inhibited OC production, reduced RANKL activity, and increased OPG activity, appear to induce the occurrence of BRONJ. Figure 7 presents a hypothetical three-step model detailing the basic stages for the development of BRONJ at AIOJ/BMD/FDOJ areas. Regions with fatty-degenerative changes may be the focal point for the subsequent development of BRONJ, as such changes may constitute an additional risk factor. This is consistent with the hypothesis described in the literature, whereby bone necrosis precedes clinically evident ONJ that is exposed through the oral mucosa.78,105 Regions featuring subclinical changes and necrotic bone may represent significant risk factors in the development of BRONJ.104 Further, it is known that patients at each stage exhibit a very different bone composition.104

Figure 7 Three-step model for the development of BRONJ beginning with undetected AIOJ/BMD/FDOJ followed by the development of the NE-BRONJ variant, and finally by BRONJ.Notes: Exposed bone BNOJ (left panel). Bony sequestrum BRONJ (right panel). Figure courtesy of Professor J Bouquot.

The prevention of BRONJ is of paramount importance and has been repeatedly emphasized.106108 Thus, BPs should not be regarded as the sole cause of osteonecrosis. The results of this study indicate that unresolved areas of wound healing at extraction sites especially in former wisdom tooth areas may directly contribute to the pathogenesis of BRONJ. Other research has already described the involvement of the jaw in BRONJ as opposed to other bone sites.109 This may be because BPs are preferentially deposited in bones with high turnover rates such as the jawbone. The jawbone also presents with hidden conditions that according to our hypothesis share common characteristics with those found in AIOJ/BMD/FDOJ. Under the influence of BPs, areas of AIOJ/BMD/FDOJ may develop the pathological features of BRONJ. Efforts to prevent BRONJ, therefore, should not ignore the fact that BRONJ and AIOJ/BMD/FDOJ share similar osteoimmunological characteristics with respect to amplifying or reversing derailed signal cascades. Since AIOJ/BMD/FDOJ represent chronic, subclinical states, the sudden formation of BRONJ may be interpreted as a subsequent acute event. The early detection of BRONJ (as well as AIOJ/BMD/FDOJ) using X-ray techniques appears to be difficult. A new risk-benefit analysis should be considered: Patients should be screened for hidden oral risk factors, such as AIOJ/BMD/FDOJ. Thus, TAU may be used to measure bone density and fill this diagnostic gap. When parenteral BP therapy is administered, periodontal prophylaxis and tooth restoration should take precedence;110,111 furthermore, AIOJ/BMD/FDOJ should be diagnosed first, preferably (and accurately) with TAU-n, and then surgically eliminated. The formation of difficult-to-treat BRONJ could be avoided in certain cases if the exacerbation of pre-existing areas of AIOJ/BMD/FDOJ is prevented before initiating anti-tumorigenic BP therapy. Surgical opening of the cortex, removal of ischemic marrow, and accompanying wound care represent the only way to address cases of AIOJ/BMD/FDOJ.112 Consultation with an oncologist is mandatory, as the oncologist may insist on radiation therapy and the prevention of osteoradionecrosis of the jawbones via tooth restoration. To the best of our knowledge, we have highlighted, for the first time, the possible impact chains flowing from AIOJ/BMD/FDOJ and leading to the development of NE-BRONJ and further to exposed BRONJ. We also support the hypothesis presented herein with scientific data from the available literature. Due to the lack of clinical studies investigating these impact chains, multiple studies are necessary to elucidate the hypothesized relationships.

AIOJ, aseptic-ischemic osteonecrosis of the jawbone; BMD, bone marrow defects; BRONJ, bisphosphonate (BP)-related osteonecrosis of the jaw; CBCT, cone beam computed tomography; CCL5, chemokine (C-C motif) ligand 5; DVT, digital volume tomography; FDOJ, fatty-degenerative osteonecrosis/osteolysis of the jawbone; HU, hounsfield units; OPG, orthopantomogram; R/C, RANTES/CCL5; RANTES, regulated on activation, normal T cell expressed and secreted; TAU, transalveolar ultrasonography; TAU-n, new transalveolar ultrasonography device.

Hereby we confirm that written informed consent has been provided by the patient to have the case details and any accompanying images published. The data were collected as part of the normal everyday medical care of the patients and evaluated retrospectively. Institutional approval was not required to publish the case details.

English language editing of this manuscript was provided by Journal Prep Services. Additional English language editing was provided by Natasha Gabriel.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The corresponding author, Johann Lechner, is the holder of a patent used in the TAU-n apparatus and its associated software and reports a patent CaviTAU licensed to Dr. Johann Lechner. Bernd Zimmermann is an employee of QINNO. The authors report no other potential conflicts of interest for this work.

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46. Schoutens A, Arlet J, Gardeniers J, Hughes S, editors. Bone Circulation and Vascularization in Normal and Pathological Conditions. New York, NY: Plenum Press; 1993.

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48. Favia G, Pilolli GP, Maiorano E. Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy. Bone. 2009;45:406413. doi:10.1016/j.bone.2009.05.008.

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[Full text] Osteonecrosis of the Jaw Beyond Bisphosphonates: Are There Any Unknown | CCIDE - Dove Medical Press

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Adipose Derived Stem Cell Therapy Market to Register Unwavering Growth During in Global by 2026 | BioRestorative Therapies, Inc., Celltex Therapeutics…

Adipose Derived Stem Cell Therapy Market Research Report 2020 This Report Is Comprised of Market Data Derived from Primary as Well As Secondary Research Techniques. The Points Covered in The Report Are Primarily Factors Which Are Considered to Be Market Driving Forces. The Report Aims to Deliver Premium Insights, Quality Data Figures and Information in Relevance with Aspects Such as Market Scope, Market Size, Market Share, Market Segments Including Types of Products and Services, Application Areas, Geographies As Well. It presents a 360-degree overview of the competitive landscape of the industries. SWOT analysis has been used to understand the Strength, Weaknesses, Opportunities, and threats in front of the businesses. Thus, helping the companies to understand the threats and challenges in front of the businesses. Adipose Derived Stem Cell Therapy market is showing steady growth and CAGR is expected to improve during the forecast period.

Adipose derived stem cells (ADSCs) are stem cells derived from adipocytes, and can differentiate into variety of cell types. ADSCs have multipotency similar to bone marrow mesenchymal stem cells, thus ADSCs substitute for bone marrow as a source of stem cells. Numerous manual and automatic stem cell separation procedures are adopted in order to separate adipose stem cells (ASCs) from adipose tissue. Flow cytometry can also be used to isolate ADSCs from other stem cells within a cell solution.

The top manufacturer with company profile, sales volume, and product specifications, revenue (Million USD) and market share BioRestorative Therapies, Inc., Celltex Therapeutics Corporation, Antria, Inc., Cytori Therapeutics Inc., Intrexon Corporation, Mesoblast Ltd., iXCells Biotechnologies, Pluristem Therapeutics, Inc., Thermo Fisher Scientific, Inc., Tissue Genesis, Inc., Cyagen US Inc., Celprogen, Inc., and Lonza Group, among others.

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The Report Incorporates Valuable Differentiating Data Regarding Each of The Market Segments. These Segments Are Studied Further on Various Fronts Including Past Performance, Market Size Contributions, Market Share, Expected Rate of Growth, And More.

SynopsisAdipose Derived Stem Cell Therapy Market Research Report covers insights ofAdipose Derived Stem Cell Therapy industry over past five to eight years and forecast until 2018-2026.Adipose Derived Stem Cell Therapy Market report helps to analyze competitive developments such as joint ventures, strategic alliances, mergers and acquisitions, new product developments, and research and developments in the GlobalAdipose Derived Stem Cell Therapy Market 2018 Industry Trend and Forecast 2026.

In the end, the report makes some important proposals for a new project ofAdipose Derived Stem Cell Therapy Industry before evaluating its feasibility. Overall, the report provides an in-depth insight of the globalAdipose Derived Stem Cell Therapy industry covering all important parameters.

Adipose Derived Stem Cell Therapy Market Geographical Segment

In Conclusion, Adipose Derived Stem Cell Therapy Market Report Presents the Descriptive Analysis of the Parent Market Based On Elite Players, Present, Past and Futuristic Data Which Will Serve as A Profitable Guide for All the Adipose Derived Stem Cell Therapy Market Competitors.

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Formulate Significant Competitor Information, Analysis, and Insights to Improve R&D Strategies of Adipose Derived Stem Cell Therapy Market. Identify Emerging Players of Adipose Derived Stem Cell Therapy Market with Potentially Strong Product Portfolio and Create Effective Counter Strategies to Gain Competitive Advantage. Identify and Understand Important and Diverse Types of Adipose Derived Stem Cell Therapy Market Under Development. Develop Adipose Derived Stem Cell Therapy Market Entry and Market Expansion Strategies. Plan Mergers and Acquisitions Effectively by Identifying Major Players, CAGR, SWOT Analysis with The Most Promising Pipeline of Adipose Derived Stem Cell Therapy Market. In-Depth Analysis of the Products Current Stage of Development, Territory and Estimated Launch Date of Adipose Derived Stem Cell Therapy Market.

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Global Adipose Derived Stem Cell Therapy Market: Competitive Landscape

In order to keep their position in the market and combat competition, manufacturers across the globe have developed and implemented marketing strategies. These strategies include mergers and acquisitions, collaboration, product innovation, and others. The researchers have studied these strategies to understand the current market trend boosting the market globally. Furthermore, it also helps anticipate how these trends are expected to affect the global market.

Global Adipose Derived Stem Cell Therapy Market: Segment Analysis

The researchers have segmented the market into product types and end-users as they are the two most crucial units of the market. The product type segment helps to understand the product observing heavy demand in the market during the forecast years. The chapter on the end-user segment helps determine where the application of the product is rising and reporting immense demand. This helps the reader anticipate where the market is growing presently and the direction it will take in the future.

The Adipose Derived Stem Cell Therapy Market report considers the following years to predict market growth:

Historic Year: 2014 2018Base Year: 2018Estimated Year: 2019Forecast Year: 2019 2029


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Further, in theAdipose Derived Stem Cell Therapy Market research report, the following points are included along with an in-depth study of each point:

Production Analysis Production of theAdipose Derived Stem Cell Therapy is analyzed with respect to different regions, types, and applications. Here, price analysis of variousAdipose Derived Stem Cell Therapy Market key players is also covered.

Sales and Revenue Analysis Both, sales and revenue are studied for the different regions of the globalAdipose Derived Stem Cell Therapy Market. another major aspect, price, which plays an important part in the revenue generation is also assessed in this section for the various regions.

Supply and Consumption In continuation with sales, this section studies supply and consumption for theAdipose Derived Stem Cell Therapy Market. This part also sheds light on the gap between supply and consumption. Import and export figures are also given in this part.

Other analyses Apart from the information, trade and distribution analysis for theAdipose Derived Stem Cell Therapy Market, the contact information of major manufacturers, suppliers and key consumers are also given. Also, SWOT analysis for new projects and feasibility analysis for new investments are included.

In continuation with this data, the sale price is for various types, applications and regions is also included. TheAdipose Derived Stem Cell Therapy Market for major regions is given. Additionally, type wise and application wise consumption figures are also given.

(*If you have any special requirements, please let us know and we will offer you the report as you want.)

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Adipose Derived Stem Cell Therapy Market to Register Unwavering Growth During in Global by 2026 | BioRestorative Therapies, Inc., Celltex Therapeutics...

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Adipose Derived Stem Cell Therapy Market 2018: Production, Sales, Supply, Demand, Analysis and Forecast To 2026 | BioRestorative Therapies, Inc.,…

The Global Adipose Derived Stem Cell Therapy Market report provides a holistic evaluation of the market for the forecast period (20192025). The report comprises various segments as well as an analysis of the trends and factors that are playing a substantial role in the market. These factors; the market dynamics involve the drivers, restraints, opportunities and challenges through which the impact of these factors in the market are outlined. The drivers and restraints are intrinsic factors whereas opportunities and challenges are extrinsic factors of the market. The Global Adipose Derived Stem Cell Therapy Market study provides an outlook on the development of the market in terms of revenue throughout the prognosis period.

In order to present an executive-level model of the market and its future perspectives, the Adipose Derived Stem Cell Therapy Market report presents a clear segmentation based on different parameters. The factors that affect these segments are also discussed in detail in the report.

Adipose derived stem cells (ADSCs) are stem cells derived from adipocytes, and can differentiate into variety of cell types. ADSCs have multipotency similar to bone marrow mesenchymal stem cells, thus ADSCs substitute for bone marrow as a source of stem cells. Numerous manual and automatic stem cell separation procedures are adopted in order to separate adipose stem cells (ASCs) from adipose tissue. Flow cytometry can also be used to isolate ADSCs from other stem cells within a cell solution.

Major Players included in this report are as follows BioRestorative Therapies, Inc., Celltex Therapeutics Corporation, Antria, Inc., Cytori Therapeutics Inc., Intrexon Corporation, Mesoblast Ltd., iXCells Biotechnologies, Pluristem Therapeutics, Inc., Thermo Fisher Scientific, Inc., Tissue Genesis, Inc., Cyagen US Inc., Celprogen, Inc., and Lonza Group, among others.

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Adipose Derived Stem Cell Therapy Market: Regional analysis includes:

The study will also feature the key companies operating in the industry, their product/business portfolio, market share, financial status, regional share, segment revenue, SWOT analysis, key strategies including mergers & acquisitions, product developments, joint ventures & partnerships an expansions among others, and their latest news as well. The study will also provide a list of emerging players in the Adipose Derived Stem Cell Therapy Market.

Adipose Derived Stem Cell Therapy Market scope

A basic summary of the competitive landscape A detailed breakdown of the regional expanse A short overview of the segmentation

Furthermore, this study will help our clients solve the following issues:

Cyclical dynamics We foresee dynamics of industries by using core analytical and unconventional market research approaches. Our clients use insights provided by us to maneuver themselves through market uncertainties and disruptions.

Identifying key cannibalizes Strong substitute of a product or service is the most prominent threat. Our clients can identify key cannibalizes of a market, by procuring our research. This helps them in aligning their new product development/launch strategies in advance.

Spotting emerging trends Our Ecosystem offering helps the client to spot upcoming hot market trends. We also track possible impact and disruptions which a market would witness by a particular emerging trend. Our proactive analysis helps clients to have an early mover advantage.

Interrelated opportunities This report will allow clients to make decisions based on data, thereby increasing the chances that the strategies will perform better if not best in the real world.

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Some of the Major Highlights of TOC covers:

Adipose Derived Stem Cell Therapy Regional Market Analysis

Adipose Derived Stem Cell Therapy Production by Regions Global Adipose Derived Stem Cell Therapy Production by Regions Global Adipose Derived Stem Cell Therapy Revenue by Regions Adipose Derived Stem Cell Therapy Consumption by Regions

Adipose Derived Stem Cell Therapy Segment Market Analysis (by Type)

Global Adipose Derived Stem Cell Therapy Production by Type Global Adipose Derived Stem Cell Therapy Revenue by Type Adipose Derived Stem Cell Therapy Price by Type

Adipose Derived Stem Cell Therapy Segment Market Analysis (by Application)

Global Adipose Derived Stem Cell Therapy Consumption by Application Global Adipose Derived Stem Cell Therapy Consumption Market Share by Application (2014-2019)

Adipose Derived Stem Cell Therapy Major Manufacturers Analysis

Adipose Derived Stem Cell Therapy Production Sites and Area Served Product Introduction, Application and Specification Adipose Derived Stem Cell Therapy Production, Revenue, Ex-factory Price and Gross Margin (2014-2019)Main Business and Markets Served

Key questions answered in the report:


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Key Benefits

Major countries in each region are mapped according to individual market revenue. Comprehensive analysis of factors that drive and restrict market growth is provided. The report includes an in-depth analysis of current research and clinical developments within the market. Key players and their key developments in recent years are listed.And More.

About Coherent Market Insights

Coherent Market Insights is a prominent market research and consulting firm offering action-ready syndicated research reports, custom market analysis, consulting services, and competitive analysis through various recommendations related to emerging market trends, technologies, and potential absolute dollar opportunity.

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Adipose Derived Stem Cell Therapy Market 2018: Production, Sales, Supply, Demand, Analysis and Forecast To 2026 | BioRestorative Therapies, Inc.,...

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The #1 Best Tea for Fat Loss, According to Nutritionists | Eat This Not That – Eat This, Not That

The best tea for fat loss is any plain unsweetened tea that you choose to drink instead of some other unhealthy beverages like these belly busters: sweet tea, soda, juice, smoothies, beer, etc.). (For more background, here are 7 Ways Tea Can Help You Lose Weight.)

Disappointed with that answer? Don't be. It's the honest truth: If you are looking for a magic bullet for weight loss, you won't find it in a teacup. Drinking tea alone is no more effective than any other fat-loss technique if you don't combine it with other healthy eating practices. In other words, a cuppa plain tea won't cancel out the tea biscuits.

That said, unsweetened tea is second only to water as the weight loss beverage most recommended by nutritionists and other health experts. For good reason: Plain tea contains zero calories and is rich in natural compounds that have many health benefits.

But which is the best type of tea for fat loss? One could argue that green tea is tops simply because green tea has been clinically studied more than any other kind of tea. Many studies have shown that the bounty of antioxidants in green tea may reduce inflammation and lower the risk of heart disease, diabetes, and cancer. Research suggests that special compounds called catechins and the caffeine in green tea stimulate thermogenesis and boost metabolism. Other studies correlate drinking several cups of green tea a day for longer than six weeks with weight loss.

Of course, any calorie-free tea can help with weight loss if it replaces a high-calorie beverage. To get the biggest fat-loss benefit from tea, pick your favorite from these tea types recommended by nutritionists and pair it with one of The 6 Best Diets That Will Make You Live Longer.

"One of the best teas that support fat loss is black tea," says Tiffany Joy Yamut, a registered nurse, certified nutritionist, and co-founder of the keto diet resource Ketogenic Buddies. Black tea is made from leaves of the same plant from which green tea is made:Camellia sinensis. The big difference is how it's processed. Black tea leaves are exposed to air and allowed to oxidize into that trademark dark brown color. "A 2016 study published in Molecules showed that polyphenols in black tea can prevent obesity; one of its mechanisms is that it inhibits lipid (fat) absorption," says Yamut. "I follow a low-carbohydrate diet and black tea suits my lifestyle well since it contains no carbs plus some caffeine to jumpstart my metabolism." However, black tea isn't for everyone, she cautions. "Tea has caffeine, which can worsen gastroesophageal reflux disease symptoms."

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"Any plain tea without sugar, honey, and syrups is great for weight loss," says Amanda A Kostro Miller, RD, LDN, who serves on the advisory board for Fitter Living. "Not only can you get fluid for hydration, [but you're also] filling up your stomach for only a few calories." If you run out of tea, you can always hydrate for fat loss by knowing This Is How Much Water You Need to Drink for Weight Loss.

This traditional Chinese tea, also known as black dragon, is made from the leaves of the same plant that yields green and black teas. The only difference is that unlike green tea, oolong is allowed to oxidize, but not long enough to turn into black tea. The result is a flavor that is less bitter than black tea, lighter, and more "grassy." Oolong tea has not been studied to the extent of green tea, but studies do point to its potential as a weight-loss beverage. In one study published in the Chinese Journal of Integrative Medicine, 102 overweight people consumed 8 grams of oolong tea, or about four cups a day for six weeks. Measuring body fat and body weight levels, researchers found that 70% of the heaviest subjects lost a little more than 2 pounds while 22% lost more than 6.5 pounds. Also, 12% of subjects experienced a decrease in subcutaneous fat.

Plant-based nutritionist Stephanie Mantilla's favorite weight-loss tea is caffeine-free rooibos from South Africa. Studies have shown that the red tea "helps block the creation of fat cells and increase metabolism," says the founder of Plant Prosperous.

Because the herbal tea is high in antioxidants and contains anti-inflammatory properties, one South African researcher is investigating its effect on fat stem cells. Dr. Hanl Sadie-Van Gijsen of the Division of Medical Physiology at Stellenbosch University is seeking to addressthe inflammation and oxidative stress within the fat tissue to relieve whole-body inflammation and insulin resistance. She says inflammation and oxidative stress are hallmarks of "dysfunctional fat," and responsible for many of the diseases associated with obesity.

Peppermint is a time-honored home remedy for indigestion, and it is believed to be a metabolism booster. "This tea's antifungal nature is also responsible for its ability to help improve digestive health," says nutritionist Lisa Richards, author of The Candida Diet. "A cup of peppermint tea after a meal can help alleviate gas and bloating while also speeding along digestion and potentially metabolism through this means as well."

Ginger tea is a favorite of Trista Best, RD, a registered dietitian with Balance Once Supplements, due to its robust flavor and antioxidant richness. "Ginger is unique for weight loss in that it contains compounds known as gingerols and shogaols, compounds that reduce the oxidative stress that exacerbates obesity," she says. "This damage occurs at the cellular level and once those damaged cells replicate the body's natural processes that maintain homeostasis can become disrupted leading to decreased metabolism, energy, and more."

A number of experts told us that green tea, matcha (a powdered green tea), and green tea extract are considered to be some of the best for supporting healthy weight loss because they are particularly high in antioxidants and anti-inflammatory compounds including EGCG (epigallocatechin-3-gallate).

"EGCG seems to help block the formation of new fat cells and may also reduce hunger and cravings, plus caffeine in green tea has appetite-decreasing effects," says Dr. Josh Axe, D.N.M., CNS, founder of

This catechin abundant in green tea is also thought to improve recovery from exercise, boosting metabolism and potentially reducing fat storage. "Antioxidants found in green tea can support metabolic health by lowering oxidative stress, plus they keep blood sugar levels more balanced which is beneficial for controlling fat storage," says Axe.

"The ECGC in green tea can deactivate the genetic triggers for diabetes and obesity," says Kelly Choi, author of the Eat This, Not That! book The 7-Day Flat-Belly Tea Cleanse.

To learn how drinking green tea changed Choi's life, read I Tried a Tea Cleanse for 7 Days and This is What Happened.

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The #1 Best Tea for Fat Loss, According to Nutritionists | Eat This Not That - Eat This, Not That

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Papaya leaf juice: Health benefits, how to make and the right way to consume – Times of India

Carica papaya, commonly called papaya, is grown in the tropical regions and is one of the most loved fruits by everyone. This yellowish-orange fruit is full of nutrients, which is great for our health. It has antibacterial properties and almost every part of the papaya plant can be used. Apart from the fruit, the most consumed part of the papaya plant is papaya leaf. Papaya leaf juice is the most desi remedy used for increasing the platelet count. It has gained immense popularity in the last few years due to its various health benefits. It is rich in enzymes like papain and chymopapain, which aids digestion, prevents bloating and other digestive disorders. The alkaloid compound in it works effectively against fighting dandruff and balding. The leaves contain a high amount of vitamin A, C. E, K and B.Papaya leaf preparations, such as teas, extracts, juices and tablets are often used to treat illness and promote health.

Here are seven health benefits of papaya leaf juice and an easy way to prepare it.

Can treat dengue symptomsPapaya leaf juice is most commonly used to treat symptoms associated with dengue fever. Common symptoms of dengue include fever, fatigue, headaches, nausea, skin rashes and vomiting. In some severe cases, it can also result in reduced platelet levels, which can increase the risk of bleeding and can turn potentially fatal if left untreated.

Currently, there is no treatment for dengue and papaya leaf juice is one of the most commonly used treatment methods.

Three studies that included hundreds of people suffering from dengue found that papaya leaf extract helped in increasing the blood platelet levels drastically.

Can help in balancing blood sugar levelPapaya leaf juice is often used as a natural medicine for treating diabetes and thus improving the blood sugar levels.

Studies conducted on mice have found that papaya leaf extract is full of antioxidants and blood sugar-lowering effects. It helps by protecting the insulin-producing cells in the pancreas from damage and premature death.

But no research on the same has been conducted on humans.

Supports digestive healthPapaya leaf teas are used to alleviate digestive symptoms like gas, bloating and heartburn. Papaya leaf contains fibre, which supports digestive health. It can break down the large protein into smaller and easier to digest proteins and amino acids. It also helps in treating problems like constipation, heartburn and alleviating symptoms in people with irritable bowel syndrome.

These findings are limited to anecdotal reports and there is no guarantee that it will improve your digestion. But then there is no harm in trying.

Has anti-inflammatory effectsPapaya leaf preparation is used to treat a range of internal and external inflammatory conditions, including muscle aches and joint pain.

A study found that papaya leaf extract significantly reduced inflammation and swelling in the paws of rats with arthritis.

Can support hair growthApplication of papaya leaf juice on the scalp can promote hair growth and hair health. But the evidence proving the same is very limited. Studies suggest that high levels of oxidative stress in the body can contribute to hair loss. Thus, eating an antioxidant-rich diet can help alleviate oxidative stress and improve hair growth.

Papaya juice has antifungal properties, which can control the dandruff-causing fungus called Malassezia.

Can promote healthy skinPapaya leaf is consumed orally and applied on the skin for soft and clean skin. It has a protein dissolving enzyme called papain that works as an exfoliant and thus helps remove dust and dead skin cells. It also helps in reducing the occurrence of clogged pores, ingrown hair and acne.

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Papaya leaf juice: Health benefits, how to make and the right way to consume - Times of India

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Industry News: RheinCell Therapeutics achieves milestone GMP certification to manufacture cord blood-derived iPSCs for safe and compliant cell…

RheinCell Therapeutics GmbH, a developer and manufacturer of human induced pluripotent stem cells (iPSCs) as starting materials for cell therapies, has announced it has received Good Manufacturing Practice (GMP) certification and Manufacturing Authorization. This marks a landmark achievement for RheinCell, which is now among a select few iPSCs manufacturers to have received the critical certification.

The certificate and accompanying manufacturing permit which were granted following inspection of RheinCells manufacturing facilities in September 2020 confirm that the company's site follows the GMP principles of the European Union for human medicinal products (2003/94/EC), including requirements for chemical, physical, and biological quality control testing.

"We have reached another milestone in the evolution of our company one that was borne from the foresight of our manufacturing and quality control teams, and the tremendous work of everyone involved in building an efficient production strategy," said Jrgen Weisser, CEO of RheinCell. "RheinCell is now one of very few commercial enterprises worldwide that are certified to produce iPSCs a critical starting material for stem cell-based therapies in a regulated and GMP-compliant process and environment."

Heading up the certification efforts was Dr. Katja Aschermann, COO of RheinCell. "At RheinCell, we are proud to implement state-of-the-art, GMP-compliant manufacturing processes to meet the needs of our international customers for ready-to-use, fully characterized clinical-grade iPSC lines," explained Aschermann.

The GMP certification and Manufacturing Authorization pave the way for the company to deliver fully characterized clinical-grade iPSCs that are derived from human cord blood cells for the development of cell-based therapies. Furthermore, RheinCell has the technology, facilities, know-how and processes to manufacture, expand, differentiate, and cryopreserve these cell lines according to specific development needs.

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Industry News: RheinCell Therapeutics achieves milestone GMP certification to manufacture cord blood-derived iPSCs for safe and compliant cell...

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