InGeneron has been conducting research in stem cells and regenerative medicine for more than 15 years. Find a selection of our recent pre-clinical and clinical publications below:
Abstract – : (1) Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of prospective patients and stakeholders in healthcare. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusions regarding the efficacy of this treatment modality. It is possible that a separate meta-analysis based on an independent, systematic assessment of clinical studies on the management of pkOA with stem cells may reach a different conclusion. (2) Methods: PubMed, Web of Science, and the Cochrane Library were systematically searched for clinical studies and meta-analyses of clinical studies on the management of pkOA with stem cells. All clinical studies and meta-analyses identified were evaluated in detail, as were all sub-analyses included in the meta-analyses. (3) Results: The inconsistent conclusions regarding the efficacy of treating pkOA with stem cells in the 19 assessed meta-analyses were most probably based on substantial differences in literature search strategies among different authors, misconceptions about meta-analyses themselves, and misconceptions about the comparability of different types of stem cells with regard to their safety and regenerative potential. An independent, systematic review of the literature yielded a total of 183 studies, of which 33 were randomized clinical trials, including a total of 6860 patients with pkOA. However, it was not possible to perform a scientifically sound metaanalysis. (4) Conclusions: Clinicians should interpret the results of the 19 assessed meta-analyses of clinical studies on the management of pkOA with stem cells with caution and should be cautious of the conclusions drawn therein. Clinicians and researchers should strive to participate in FDA and/or EMA reviewed and approved clinical trials to provide clinically and statistically valid efficacy.
Abstract – Recently, the management of musculoskeletal disorders with the patients’ own stem cells, isolated from the walls of small blood vessels, which can be found in great numbers in the adipose tissue, has received considerable attention. The use of these autologous, unmodified stem cells can be seamlessly integrated into modern orthopedic treatment concepts, which can be understood as the optimization of a process which – albeit less efficiently – also takes place physiologically. Accordingly, this new safe and effective type of treatment is attractive in terms of holistic thinking and personalized medicine.
Abstract – A certain cell type can be isolated from different organs in the adult body that can differentiate into ectoderm, mesoderm, and endoderm, providing significant support for the existence of a certain type of small, vascular-associated, pluripotent stem cell ubiquitously distributed in all organs in the adult body (vaPS cells). These vaPS cells fundamentally differ from embryonic stem cells and induced pluripotent stem cells in that the latter possess the necessary genetic guidance that makes them intrinsically pluripotent. In contrast, vaPS cells do not have this intrinsic genetic guidance, but are able to differentiate into somatic cells of all three lineages under guidance of the microenvironment they are located in, independent from the original tissue or organ where they had resided. These vaPS cells are of high relevance for clinical application because they are contained in unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs). The latter can be obtained from and re-applied to the same patient at the point of care, without the need for further processing, manipulation, and culturing. These findings as well as various clinical examples presented in this paper demonstrate the potential of UA-ADRCs for enabling an entirely new generation of medicine for the benefit of patients and healthcare systems.
Abstract – Current clinical treatment options for symptomatic, partial-thickness rotator cuff tear (sPTRCT) offer only limited potential for true tissue healing and improvement of clinical results. In animal models, injections of adult stem cells isolated from adipose tissue into tendon injuries evidenced histological regeneration of tendon tissue. However, it is unclear whether such beneficial effects could also be observed in a human tendon treated with fresh, uncultured, autologous, adipose derived regenerative cells (UA-ADRCs). A specific challenge in this regard is that UA-ADRCs cannot be labeled and, thus, not unequivocally identified in the host tissue. Therefore, histological regeneration of injured human tendons after injection of UA-ADRCs must be assessed using comprehensive, immunohistochemical and microscopic analysis of biopsies taken from the treated tendon a few weeks after injection of UA-ADRCs.
Abstract – Due to their capacity to self-renew, proliferate and generate multi-lineage cells, adult-derived stem cells offer great potential in regenerative therapies to treat maladies such as diabetes, cardiac disease, neurological disorders and orthopedic injuries. Commonly derived from adipose tissue, the stromal vascular fraction (SVF), a heterogeneous cell population enriched with mesenchymal stem cells (MSCs), has garnered interest as a cellular therapy due to ease of accessibility as an autologous, point-of-care application. However, the heterogeneous cell population within SVF is not historically taken into consideration when injecting into patients. Here, we characterized SVF, determined its safety and verify its therapeutic effects in a NOD/scid mouse model of articular injury. SVF were isolated from lipoaspirates utilizing a commercially available system (InGeneron Inc.), while MSCs were isolated from SVF via cell culture. Flow cytometry showed that neither age nor BMI affects the frequency of progenitor cells-like (CD31+CD34+), immune cells-like (CD4+) T cells, (CD14+) monocytes and total number of cells obtained. However, there was a negative correlation between donor BMI and MSC frequency within the SVF. ELISAs showed that following LPS activation in SVF, there were low levels of TNF-α and high levels of IL-10 secreted. However, T cell activation with anti-CD3 or anti-CD3+ anti-CD28, while leading to expected high levels of IFN-γ, did not lead to significant levels of TGF-β. PCR analysis showed no significant numbers of cells outside the joint 1-hour post injection, moreover, no engraftment or abnormal growth in other organs 60-days post injection. Finally, both cell populations were able to ameliorate disease progression, as confirmed by the increase in movement of treated groups compared to injured groups. Noteworthy, the histological analysis indicated that there was no cartilage growth, suggesting an alternative therapeutic mechanism to cartilage regeneration.
Abstract – It has become practically impossible to survey the literature on cells derived from adipose tissue for regenerative medicine. The aim of this paper is to provide a comprehensive and translational understanding of the potential of UA-ADRCs (uncultured, unmodified, fresh, autologous adipose derived regenerative cells isolated at the point of care) and its application in regenerative medicine. We provide profound basic and clinical evidence demonstrating that tissue regeneration with UA-ADRCs is safe and effective. ADRCs are neither ‘fat stem cells’ nor could they exclusively be isolated from adipose tissue. ADRCs contain the same adult stem cells ubiquitously present in the walls of blood vessels that are able to differentiate into cells of all three germ layers. Of note, the specific isolation procedure used has a significant impact on the number and viability of cells and hence on safety and efficacy of UA-ADRCs. Furthermore, there is no need to specifically isolate and separate stem cells from the initial mixture of progenitor and stem cells found in ADRCs. Most importantly, UA-ADRCs have the physiological capacity to adequately regenerate tissue without need for more than minimally manipulating, stimulating and/or (genetically) reprogramming the cells for a broad range of clinical applications. Tissue regeneration with UA-ADRCs fulfills the criteria of homologous use as defined by the regulatory authorities.
Hurd, J., Facile, T.R., Weiss, J.L., Hayes, M., Hayes, M., Furia, J., Maffulli, N., Winnier, G.E., Alt, C., Schmitz, C., Alt, E. and Lundeen, M., 2020. Journal of Orthopaedic Surgery and Research, 15(1), 1-18.
Abstract – A certain cell type can be isolated from different organs in the adult body that can differentiate into ectoderm, mesoderm, and endoderm, providing significant support for the existence of a certain type of small, vascular-associated, pluripotent stem cell ubiquitously distributed in all organs in the adult body (vaPS cells). These vaPS cells fundamentally differ from embryonic stem cells and induced pluripotent stem cells in that the latter possess the necessary genetic guidance that makes them intrinsically pluripotent. In contrast, vaPS cells do not have this intrinsic genetic guidance, but are able to differentiate into somatic cells of all three lineages under guidance of the microenvironment they are located in, independent from the original tissue or organ where they had resided. These vaPS cells are of high relevance for clinical application because they are contained in unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs). The latter can be obtained from and re-applied to the same patient at the point of care, without the need for further processing, manipulation, and culturing. These findings as well as various clinical examples presented in this paper demonstrate the potential of UA-ADRCs for enabling an entirely new generation of medicine for the benefit of patients and healthcare systems.
Haenel, A., Ghosn, M., Karimi, T., Vykoukal, J., Shah, D., Valderrabano, M., Schulz, D. G., Raizner, A., Schmitz, C., Alt, E. U. (2019). World Journal of Stem Cells, 11(10), 831.
Abstract – Numerous studies investigated cell-based therapies for myocardial infarction (MI). The conflicting results of these studies have established the need for developing innovative approaches for applying cell-based therapy for MI. Experimental studies on animal models demonstrated the potential of fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) for treating acute MI. In contrast, studies on the treatment of chronic MI (CMI; > 4 wk post-MI) with UA-ADRCs have not been published so far. Among several methods for delivering cells to the myocardium, retrograde delivery into a temporarily blocked coronary vein has recently been demonstrated as an effective option.
Abstract – Freshly isolated, uncultured, autologous adipose derived regenerative cells (ADRCs) have emerged as a promising tool for regenerative cell therapy. The Transpose RT system (InGeneron, Inc., Houston, TX, USA) is a system for isolating ADRCs from adipose tissue, commercially available in Europe as a CE-marked medical device and under clinical evaluation in the United States. This system makes use of the proprietary, enzymatic Matrase Reagent for isolating cells. The present study addressed the question whether the use of Matrase Reagent influences cell yield, cell viability, live cell yield, biological characteristics, physiological functions or structural properties of the ADRCs in final cell suspension. Identical samples of subcutaneous adipose tissue from 12 subjects undergoing elective lipoplasty were processed either with or without the use of Matrase Reagent. Then, characteristics of the ADRCs in the respective final cell suspensions were evaluated. Compared to non-enzymatic isolation, enzymatic isolation resulted in approximately twelve times higher mean cell yield (i.e., numbers of viable cells/ml lipoaspirate) and approximately 16 times more colony forming units. Despite these differences, cells isolated from lipoaspirate both with and without the use of Matrase Reagent were independently able to differentiate into cells of all three germ layers. This indicates that biological characteristics, physiological functions or structural properties relevant for the intended use were not altered or induced using Matrase Reagent. A comprehensive literature review demonstrated that isolation of ADRCs from lipoaspirate using the Transpose RT system and the Matrase Reagent results in the highest viable cell yield among published data regarding isolation of ADRCs from lipoaspirate.
Abstract – Novel strategies are needed for improving guided bone regeneration (GBR) in oral surgery prior to implant placement, particularly in maxillary sinus augmentation (GBR-MSA) and in lateral alveolar ridge augmentation (LRA). This study tested the hypothesis that the combination of freshly isolated, unmodified autologous adipose-derived regenerative cells (UA-ADRCs), fraction 2 of plasma rich in growth factors (PRGF-2) and an osteoinductive scaffold (OIS) (UA-ADRC/PRGF-2/OIS) is superior to the combination of PRGF-2 and the same OIS alone (PRGF-2/OIS) in GBR-MSA/LRA.
