The Centeno-Schultz Clinic is a research-based medical practice founded by Christopher J. Centeno, M.D., and John R. Schultz, M.D. . The Regenexx procedures have been studied extensively for several years and we maintain what we believe to be the world’s largest human mesenchymal stem cell re-implantation database for orthopedic purposes.

The original Regenexx-C procedure was first used as part of an IRB supervised clinical trial from 2005-2007. During this time our medical practice invested hundreds of thousands of dollars in providing investigational care, with all patients receiving before and after research-grade MRI’s. For more information on how physicians innovate versus how FDA/drug companies discover new drugs, see this link. By late 2007, once the physicians were satisfied that the procedure was working and that the complications were less than existing surgical care, the clinic began treating patients. Since that time the clinic has published many medical research papers listed in the U.S. Library of Medicine (see this link for an incomplete list). Every patient treated by us is entered into a treatment registry and will be contacted at various time points regarding the outcome of the procedure, any complications, etc…  As a result, we have extensive experience in what works and what doesn’t work.  In addition, based on our published complications papers, our procedure produces significantly fewer complications than the more invasive surgical procedures it helps many patients avoid.

In addition to peer reviewed publications, we also publish our treatment registry data online. See the most recent treatment registry data on Regenexx-SD for knee arthritis, hip arthritis analysis 1 and analysis 2 using different metrics, all shoulder patients, rotator cuff tear patients, ankle arthritis, and hand/wrist arthritis. In addition, low back sciatica outcomes on the Regenexx-PL-Disc procedure. Pre-publication data and before/after MRI case studies can often be found on the Regenexx blog.


Our Published Research on Stem Cells:

Efficacy of Autologous Bone Marrow Concentrate for Knee Osteoarthritis with and without Adipose Graft

BioMed Research International; Volume 2014, Article ID 370621,. Centeno CJ.

Introduction. We investigated the use of autologous bone marrow concentrate (BMC) with and without an adipose graft, for treatment of knee osteoarthritis (OA). Methods. Treatment registry data for patients who underwent BMC procedures with and without an adipose graft were analyzed. Pre- and posttreatment outcomes of interest included the lower extremity functional scale (LEFS), the numerical pain scale (NPS), and a subjective percentage improvement rating. Multivariate analyses were performed to examine the effects of treatment type adjusting for potential confounding factors. The frequency and type of adverse events (AE) were also examined. Results. 840 procedures were performed, 616 without and 224 with adipose graft. The mean LEFS score increased by 7.9 and 9.8 in the two groups (out of 80), respectively, and the mean NPS score decreased from 4 to 2.6 and from 4.3 to 3 in the two groups, respectively. AE rates were 6% and 8.9% in the two groups, respectively. Although pre- and posttreatment improvements were statistically significant, the differences between the groups were not. Conclusion. BMC injections for knee OA showed encouraging outcomes and a low rate of AEs. Addition of an adipose graft to the BMC did not provide a detectible benefit over BMC alone.

Clinical challenges and opportunities of mesenchymal stem cells in musculoskeletal medicine.

PM R. 2014 Jan;6(1):70-7. doi: 10.1016/j.pmrj.2013.08.612. Centeno CJ.

Abstract: The use of stem cells in orthopedics has been researched for many years, with robust animal data that show efficacy in cartilage healing, tendon repair, and intervertebral disk treatment. Early clinical data are also just starting to be published, and these results are encouraging. Safety data in large case series, some that lasted for many years, have also been published. The field of tissue engineering with stem cells in musculoskeletal impairments has the potential to reduce morbidity and improve clinical outcomes. The regulatory environment for this area of medicine is still developing.

Copyright © 2014 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved. PMID: 24439149

Amide-Type Local Anesthetics and Human Mesenchymal Stem Cells: Clinical Implications for Stem Cell Therapy.

Stem Cells Transl Med. 2014 Jan 16. [Epub ahead of print]

Amide-Type Local Anesthetics and Human Mesenchymal Stem Cells: Clinical Implications for Stem Cell Therapy.

In the realm of regenerative medicine, human mesenchymal stem cells (hMSCs) are gaining attention as a cell source for the repair and regeneration of tissues spanning an array of medical disciplines. In orthopedics, hMSCs are often delivered in a site-specific manner at the area of interest and may require the concurrent application of local anesthetics (LAs). To address the implications of using hMSCs in combination with anesthetics for intra-articular applications, we investigated the effect that clinically relevant doses of amide-type LAs have on the viability of bone marrow-derived hMSCs and began to characterize the mechanism of LA-induced hMSC death. In our study, culture-expanded hMSCs from three donors were exposed to the amide-type LAs ropivacaine, lidocaine, bupivacaine, and mepivacaine. To replicate the physiological dilution of LAs once injected into the synovial capsule, each anesthetic was reduced to 12.5%, 25%, and 50% of the stock solution and incubated with each hMSC line for 40 minutes, 120 minutes, 360 minutes, and 24 hours. At each time point, cell viability assays were performed. We found that extended treatment with LAs for 24 hours had a significant impact on both hMSC viability and adhesion. In addition, hMSC treatment with three of the four anesthetics resulted in cell death via apoptosis following brief exposures. Ultimately, we concluded that amide-type LAs induce hMSC apoptosis in a time- and dose-dependent manner that may threaten clinical outcomes, following a similar trend that has been established between these particular anesthetics and articular chondrocytes both in vitro and in vivo.

Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review.

NOTE: This article was written by an independent third party after requesting the source data for our n=339 safety paper. They reviewed that source data and concluded that it was the highest quality data reporting on safety of any paper they reviewed in the meta-analysis. As a result, it is the primary basis for many of their conclusions below.

Osteoarthritis Cartilage. 2013 Oct;21(10):1465-73. doi: 10.1016/j.joca.2013.06.025. Epub 2013 Jul 4.

Abstract

BACKGROUND: An important goal of stem cell research in orthopaedics is to develop clinically relevant techniques that could be applied to heal cartilage or joint pathology. Stem cell treatment in orthopaedics for joint pathology is promising since these cells have the ability to modulate different processes in the various tissues of the joint simultaneously. The non life-threatening nature of musculoskeletal system disorders makes safety ofstem cell therapy a necessary prerequisite.

OBJECTIVE: To systematically review the literature and provide an overview of reported adverse events (AEs) of intra-articular treatment with culture-expanded stem cells in humans.

DESIGN: A systematic literature search was performed in Pubmed, EMBASE, Web of Science and CINAHL in February 2013. AEs were reported into three categories: local/systemic, serious adverse event or AE (SAE/AE), related/unrelated.

RESULTS: 3039 Potentially eligible articles were identified of which eventually eight fulfilled our inclusion criteria. In total, 844 procedures with a mean follow-up of 21 months were analysed. Autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) were used for cartilage repair and osteoarthritis treatment in all included studies. Four SAEs were reported by the authors. One infection following bone marrow aspiration (BMA) was reported as probably related and resolved with antibiotics. One pulmonary embolism occurred 2 weeks after BMA and was reported as possibly related. Two tumours, both not at the site of injection, were reported as unrelated. Twenty-two other cases of possible procedure-related and seven of possible stem cell-product related adverse events (AEs) were documented. The main AEs related to the procedure were increased pain/swelling and dehydration after BMA. Increased pain and swelling was the only AE reported as related to the stem cell-product.

CONCLUSIONS: Based on current literature review we conclude that application of cultured stem cells in joints appears to be safe. We believe that with continuous caution for potential side effects, it is reasonable to continue with the development of articular stem cell therapies.

Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group.

Centeno CJ, D Freeman M.

Wien Med Wochenschr. 2013 Aug 15.

ABSTRACT

BACKGROUND: Mesenchymal stem cells (MSCs) show promising clinical potential as multipotent therapeutic agents in regenerative medicine, including a number of orthopedic applications.  Objective: To study the possible value of MSC’s injected intra-articular in patients with carpometecarpal (CMC) joint and hand osteoarthritis (OA).

METHODS: This is a prospective, case series with an untreated control that was obtained through a convenience sample. Patients underwent a bone marrow aspiration with isolation and culture expansion of MSC’s using a serum free, autologous platelet lysate. Autologous MSC’s were injected intra-articular utilizing imaging guidance. Percentage improvement, functional and visual analog scale data was collected via survey at pre-procedure, 3 months, 6 months, and annually.

RESULTS: Six OA patients and four controls were recruited. The mean reported pain relief was significantly higher +60% in the thumb OA group (n=6, p=.032) than in the control -18.75% (n=4). The average time reporting was 11.83 +/- 5.70 months and 9.55 +/- 6.49 months for both groups, respectively. On average, a greater than 30% reduction were observed in all VAS scale metrics (n=5), average reporting time was 13 +/-5.52 months. The majority of patients (66.7%, n=6) reported an increase in both strength and range of motion, average reporting time was 11.83 +/- 5.7 months. No complications were reported.

CONCLUSIONS:Percutaneous implantation of cultured MSCs into the carpometecarpal joint was associated with patient reported improvement in pain and function that was not seen in an untreated control. In addition, all patients within this small case series reported no complications.

A Case Series of Percutaneous Treatment of Non-Union Fractures with Autologous, Culture Expanded, Bone Marrow Derived, Mesenchymal Stem Cells and Platelet Lysate

A Case Series of Percutaneous Treatment of Non-Union Fractures with Autologous, Culture Expanded, Bone Marrow Derived, Mesenchymal Stem Cells and Platelet Lysate

Centeno CJ, Schultz JR, Cheever M, Freeman M, Robinson B, Faulkner S

Journal of Bioengineering and Biomedical Science. 2011

Abstract

Background: Current treatment options for stable non-union fractures represent major clinical challenges, and are a major health issue. Fracture treatment can take many forms, usually requiring bone grafting and/or revisions of the fracture with open reduction and internal fixation (ORIF). Conservative care options such as bone morphogenic proteins and bone stimulators are also available. The purpose of this study was to determine if culture expanded, autologous MSC’s injected into non-union fractures under c-Arm fluoroscopy could represent an alternative treatment modality in recalcitrant fracture non-unions.

This paper reports on the findings of 6 patients with fracture non-union treated with autologous MSC’s.  Patients and methods:  We evaluated 6 consecutive patients with chronic fracture non-unions. Patients consisted of 4 women and 2 men with treatment intervention at an average of 8.75 months post-fracture (range 4- 18 months, one patient fracture not included in calculation was >100 mo.).

All treated patients received autologous, culture expanded, mesenchymal stem cells injected percutaneously via fluoroscopic guidance into the site of the fracture non-union. Fracture union was evaluated with the use of follow up high-resolution x-ray and/or CT imaging. Phenotype of the culture-expanded MSCs was evaluated and quantified by flow cytometry of surface antigens.Conclusion: The results of this study support the hypothesis that autologous MSC’s delivered via percutaneous re-implantation may be an alternative modality for the non-operative treatment of recalcitrant non-union fractures.

Safety and Complications Reporting Update on the Re-implantation of Culture-Expanded Mesenchymal Stem Cells using Autologous Platelet Lysate Technique.

Safety and Complications Reporting Update on the Re-implantation of Culture-Expanded Mesenchymal Stem Cells using Autologous Platelet Lysate Technique.

Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B, Hanson R.–Curr Stem Cell Res Ther. 2011 Oct 17. 

Source

The Centeno-Schultz Clinic, Broomfield, Colorado, USA.

Abstract

Mesenchymal stem cells (MSCs) hold great promise as therapeutic agents in regenerative medicine. Numerous animal studies have documented the multipotency of MSCs, showing their capabilities for differentiating into orthopedic tissues such as muscle, bone, cartilage, and tendon. However, the safety of culture expanded MSC’s for human use has only just begun to be reported. Methods: Between 2006 and 2010, two groups of patients were treated for various orthopedic conditions with culture-expanded, autologous, bone marrow-derived MSCs (group 1: n=50; group 2: n=290-one patient in both groups). Cells were cultured in monolayer culture flasks using an autologous platelet lysate technique and re-injected into peripheral joints or into intervertebral discs with use of c-arm fluoroscopy. While both groups had prospective surveillance for complications, Group 1 additionally underwent 3.0T MRI tracking of the re-implant sites. Results: The mean age of patients treated was 53 +/- 13.85 years; 214 were males and 125 females with mean follow-up time from any procedure being 435 days +/- 261 days. Number of contacts initiated based on time from first procedure was 482 at 3 months, 433 at 6 months, 316 contacts at 12 months, 110 contacts at 24 months, and 22 contacts at 36 months. For Group 1, 50 patients underwent 210 MRI surveillance procedures at 3 months, 6 months, 1 year and 2 years which failed to demonstrate any tumor formation at the re-implant sites. Formal disease surveillance for adverse events based on HHS criteria documented significantly less morbidity than is commonly reported for more invasive surgical procedures, all of which were either self-limited or were remedied with therapeutic measures. Two patients were diagnosed with cancer out of 339 patients treated since study inception; however, this was almost certainly unrelated to the MSC therapy and the neoplasm rate in similar to that seen in the U.S. Caucasian population. Knee outcome data was collected on a subset of patients. Here, >75% improvement was reported in 41.4% while decreasing the improvement threshold to >50% improvement, 63.2% reported an improvement. At an average reporting time of 11.3 months from first procedure average reported relief in the knee sample equaled 53.1% (n=133 reporting). Conclusions: Using both intensive high field MRI tracking and complications surveillance in 339 patients, no neoplastic complications were detected at any stem cell re-implantation site. These findings are consistent with our prior publication and other published reports that also show no evidence of malignant transformation in vivo, following implantation of MSCs for orthopedic use.

Osteoblastic differentiation of human and equine adult bone marrow-derived mesenchymal stem cells when BMP-2 or BMP-7 homodimer genetic modification is compared to BMP-2/7 heterodimer genetic modification in the presence and absence of dexamethasone.

Osteoblastic differentiation of human and equine adult bone marrow-derived mesenchymal stem cells when BMP-2 or BMP-7 homodimer genetic modification is compared to BMP-2/7 heterodimer genetic modification in the presence and absence of dexamethasone.

Carpenter RS, Goodrich LR, Frisbie DD, Kisiday JD, Carbone B, McIlwraith CW, Centeno CJ, Hidaka C.

Orthopaedic Research Center, Colorado State University, Fort Collins, Colorado 80523.

–J Orthop Res. 2010 Mar 22

Abstract

Bone marrow-derived mesenchymal stem cells (BMDMSCs) have been targeted for use in enhancement of bone healing; and their osteogenic potential may be further augmented by genes encoding bone morphogenetic proteins (BMP’s). The purpose of this study was to compare the effect of genetic modification of human and equine BMDMSCs with BMP-2 or -7 or BMP-2 and -7 on their osteoblastogenic differentiation in the presence or absence of dexamethasone. The BMDMSCs were harvested from the iliac crest of three human donors and tuber coxae of three equine donors. Monolayer cells were genetically modified using adenovirus vectors encoding BMP-2, -7 or both and cultured in the presence or absence of dexamethasone. Expression of BMPs was confirmed by enzyme linked immunosorbent assay (ELISA). To evaluate osteoblastic differentiation, cellular morphology was assessed every other day and expression and secretion of alkaline phosphatase (ALP), as well as expression levels of osteonectin (OSTN), osteocalcin (OCN), and runt-related transcription factor-2 (Runx2) were measured for up to 14 days. Human and equine BMDMSCs showed a capacity for osteogenic differentiation regardless of genetic modification or dexamethasone supplementation. Dexamethasone supplementation was more important for osteoblastogenic differentiation of equine BMDMSCs than human BMDMSCs. Genetic modification of BMDMSCs increased ALP secretion with AdBMP-2 homodimer having the greatest effect in both human and equine cells compared to AdBMP 7 or AdBMP 2/7. BMP protein elution rates reached their maximal concentration between day 4 and 8 and remained relatively stable thereafter, suggesting that genetically modified BMDMSCs could be useful for cell-based delivery of BMPs to a site of bone formation. (c) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique.

Curr Stem Cell Res Ther. 2010 Mar;5(1):81-93.

Centeno CJSchultz JRCheever MRobinson BFreeman MMarasco W.

Abstract

ABSTRUCT: Mesenchymal stem cells (MSCs) hold great promise as therapeutic agents in regenerative medicine. Numerous animal studies have documented the multipotency of MSCs, showing their capabilities for differentiating into orthopedic tissues such as muscle, bone, cartilage, and tendon. However, the complication rate for autologous MSC therapy is only now beginning to be reported.

METHODS:

Between 2005 and 2009, two groups of patients were treated for various orthopedic conditions with culture-expanded, autologous, bone marrow-derived MSCs (group 1: n=45; group 2: n=182). Cells were cultured in monolayer culture flasks using an autologous platelet lysate technique and re-injected into peripheral joints (n=213) or into intervertebral discs (n=13) with use of c-arm fluoroscopy. While both groups had prospective surveillance for complications, Group 1 additionally underwent 3.0T MRI tracking of the re-implant sites.

RESULTS: Mean follow-up from the time of the re-implant procedure was 10.6 +/- 7.3 months. Serial MRI’s at 3 months, 6 months, 1 year and 2 years failed to demonstrate any tumor formation at the re-implant sites. Formal disease surveillance for adverse events based on HHS criteria documented 7 cases of probable procedure-related complications (thought to be associated with the re-implant procedure itself) and three cases of possible stem cell complications, all of which were either self-limited or were remedied with simple therapeutic measures. One patient was diagnosed with cancer; however, this was almost certainly unrelated to the MSC therapy.

CONCLUSIONS: Using both high field MRI tracking and general surveillance in 227 patients, no neoplastic complications were detected at any stem cell re-implantation site. These findings are consistent with other reports that also show no evidence of malignant transformation in vivo, following implantation of MSCs that were expanded in vitro for limited periods. PMID: 19951252  

Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells.

Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells.

Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D.

Regenerative Sciences Inc, Centeno-Schultz Clinic, Westminster, CO 80020, USA.

–Med Hypotheses. 2008 Dec;71(6):900-8. Epub 2008 Sep 10.

Abstract

Mesenchymal stem cells are pluripotent cells found in multiple human tissues including bone marrow, synovial tissues, and adipose tissues. They have been shown to differentiate into bone, cartilage, muscle, and adipose tissue and represent a possible promising new therapy in regenerative medicine. Because of their multi-potent capabilities, mesenchymal stem cell (MSC) lineages have been used successfully in animal models to regenerate articular cartilage and in human models to regenerate bone. The regeneration of articular cartilage via percutaneous introduction of mesenchymal stem cells (MSC’s) is a topic of significant scientific and therapeutic interest. Current treatment for cartilage damage in osteoarthritis focuses on surgical interventions such as arthroscopic debridement, microfracture, and cartilage grafting/transplant. These procedures have proven to be less effective than hoped, are invasive, and often entail a prolonged recovery time. We hypothesize that autologous mesenchymal stem cells can be harvested from the iliac crest, expanded using the patient’s own growth factors from platelet lysate, then successfully implanted to increase cartilage volume in an adult human knee. We present a review highlighting the developments in cellular and regenerative medicine in the arena mesenchymal stem cell therapy, as well as a case of successful harvest, expansion, and transplant of autologous mesenchymal stem cells into an adult human knee that resulted in an increase in meniscal cartilage volume.

Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells.

Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells.

Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D.

Regenerative Sciences Inc (RSI), Centeno-Schultz Clinic, Westminster, CO 80020, USA.–Pain Physician. 2008 May-Jun;11(3):343-53.

Abstract

BACKGROUND: The ability to repair tissue via percutaneous means may allow interventional pain physicians to manage a wide variety of diseases including peripheral joint injuries and osteoarthritis. This review will highlight the developments in cellular medicine that may soon permit interventional pain management physicians to treat a much wider variety of clinical conditions and highlight an interventional case study using these technologies OBJECTIVE: To determine if isolated and expanded human autologous mesenchymal stem cells could effectively regenerate cartilage and meniscal tissue when percutaneously injected into knees. DESIGN: Case Study SETTING: Private Interventional Pain Management practice. METHODS: An IRB approved study with a consenting volunteer in which mesenchymal stem cells were isolated and cultured ex-vivo from bone marrow aspiration of the iliac crest. The mesenchymal stem cells were then percutaneously injected into the subject’s knee with MRI proven degenerative joint disease. Pre- and post-treatment subjective visual analog pain scores, physical therapy assessments, and MRIs measured clinical and radiographic changes. RESULTS: At 24 weeks post-injection, the patient had statistically significant cartilage and meniscus growth on MRI, as well as increased range of motion and decreased modified VAS pain scores. CONCLUSION: The described process of autologous mesenchymal stem cell culture and percutaneous injection into a knee with symptomatic and radiographic degenerative joint disease resulted in significant cartilage growth, decreased pain and increased joint mobility in this patient. This has significant future implications for minimally invasive treatment of osteoarthritis and meniscal injury.

PMID: 18523506 [PubMed - indexed for MEDLINE]Free Article

Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study.

Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study.

Centeno CJ, Kisiday J, Freeman M, Schultz JR.

The Centeno-Schultz Clinic, 11080 Circle Point Road, Building 2, Suite 140, Westminster, CO 80020, USA. centenooffice@cenenoclinic.com

–Pain Physician. 2006 Jul;9(3):253-6.

Abstract

HISTORY: This is a case report of a 64-year-old white male with a 20 year history of unilateral hip pain that had become debilitating over the last several years. On intake, Harris hip score was rated as: Pain subscale = 10, Function subscale = 32, Deformity subscale = 4, Motions subscale = 4.775 with a total score of 50.8 out of 100. MRI of the affected hip showed severe degeneration with spurring, decrease in joint space, and several large subchondral cysts. The patient had been evaluated by an orthopedic surgeon and told he was a candidate for bipolar hip replacement. METHOD: Two autologous nucleated cell collections were performed from bone marrow with subsequent isolation and transfers into the intra-articular hip using a hyaluronic acid and thrombin activated platelet rich plasma scaffold. Marrow samples were processed by centrifugation and lysis techniques to isolate nucleated cells. CONCLUSION: This report describes partial by articular surface regeneration 8 weeks after intraarticular bone marrow transfer. Post-op 3.0T FGRE MRI showed neocortex formation when compared to immediate pre-op MRI and objective improvements were noted that coincided with subjective reports of improvement.

PMID: 16886034 [PubMed - indexed for MEDLINE]Free Article

[Disclaimer: The Regenexx same day procedures (-SD, -AD, -SCP, -PL-Disc, etc...) are performed in the United States. The Regenexx-C cultured stem cell procedure (herein referred to as "cultured")  is only offered through RegenexxCayman, which is an independently owned and operated medical services provider operating exclusively in the Cayman Islands and is not part of or affiliated with the Centeno-Schultz Clinic or any U.S. Regenexx Network provider. The Regenexx-C procedure licensed by RegenexxCayman is not approved by the U.S. FDA for use in the United States.]