APPLIED BIOLOGICS

Osteoarthritis: Repair of the Cartilage with Autologous Blood Therapy

Carticel, manufactured by Genzyme, is an autologous human cell product approved by the FDA in the repair of cartilage, www.carticel.com.  The cell product is part of Genzyme’s division of Biosurgery, www.genzymebiosurgery.com.  The bone marrow concentrate (BMC), produced by Harvest Technology’s bone marrow autologous concentrate system (BMAC), is a competitor cell product to Carticel for the repair and re-growth of cartilage, www.harvesttech.com. The Stowe Foundation assisted Harvest Technology to get the BMC certified by the FDA as an autologous blood product.  This gives the cellular product great flexibility in its application as a source of stem cells for use in human cell therapy.

The BMAC system itself is a unique point of care service that can produce the autologous blood product within 45 minutes of the patient’s arrival in the surgical suite.  Hence the BMAC system can be used for acute trauma care as well as the repair of chronic degeneration of the cartilage.  The BMAC system is certified by the FDA to produce an autologous blood product and has the necessary FDA certificates to be exported outside of the United States.  The Stowe Foundation has permission to provide copies of the FDA certifications associated with the Harvest Technology equipment.

In the US, Harvest Technology markets the BMAC device in the clinical laboratory or intra-operative setting to process bone marrow aspirate to produce a bone marrow concentrate (BMC) of mononuclear cells, progenitor cells, growth factors, cytokines and stem cells.  In Europe, the BMAC system and the BMC product is finding clinical applications in the treatment of osteonecrosis, bone grafts and non-unions.  Also, Harvest Technology has launched a very formal multi-center study in the US and internationally on the use of the BMAC system in the treatment of chronic limb ischemia.  They are also in negotiations with several surgical supply and distribution companies to market the BMAC system and the BMC cell product in the US for its approved indications.

The Stowe Foundation is a strategic partner with Harvest Technology to expand the use of the BMC in human cell therapy.  The Stowe Foundation supported several laboratory studies of the BMC drawn from human volunteers that confirmed the BMC was an autologous blood product.  The Stowe Foundation then sponsored several large animal studies to confirm the safety and efficacy of the BMC, an autologous blood product, in cardiac care and osteoarthritis.  But, the BMC is only one component of safe and effective stem cell therapy for a chronic condition such as heart disease and osteoarthritis.

Harvest Technology would clearly like the Stowe Foundation to launch a series of investigational studies to prove the superior nature of the BMC product compared to Carticel in cartilage repair, but that is only necessary to convince orthopedic surgeons to use Harvest Technology instead of Carticel as the source of the cellular product. That is not the business of the Stowe Foundation. We are in the business of actually treating osteoarthritis and the source of the adult stem cells is only one portion of the comprehensive immune therapy treatment program for osteoarthritis.

In fact, Genzyme specifically excludes osteoarthritis as an indicated use of its cell therapy product, Carticel.  The Carticel procedure does not deliver results in the face of chronic inflammation to the knee. The Stowe Foundation uses comprehensive immune therapy pre and post stem cell transplant to neutralize the inflammatory response of the immune system.  We call comprehensive immune therapy, Applied BioLogics.  We simply use the Harvest Technology BMAC system as the source of our adult stem cells and the BMC as the cellular product.

The Stowe Foundation has cleared all of the regulatory hurdles required to use the BMC in the treatment of osteoarthritis in our own independent Centers for Regenerative Medicine.  We are not trying to mass market the BMAC system or the BMC cell product.

Other organizations such as Duke University, as described in the memorandum, Stem Cell Therapy for Osteoarthritis, are also creating their own proprietary source of the adult stem cells.  The Duke process to achieve commercial application would have to follow a similar path to Genzyme.  Like Carticel, the fat cells being studied at Duke as the autologous cellular product are more then minimally altered before they become the stem cell product to be used in human cell therapy and the repair of cartilage. Duke’s process remains a scientific and intellectual curiosity that is many years away from commercial application.  However, they can use it in their own clinical investigations.  Duke will soon discover that stem cells are not a stand alone therapeutic agent for osteoarthritis.  That is why Carticel specifically excludes osteoarthritis from its list of indicated uses.

The Stowe Foundation owns and controls the intellectual property behind a comprehensive immune therapy protocol that only uses the BMC cellular product as one part of the comprehensive process to achieve cartilage repair.  The BMC is only used by The Stowe Foundation to stimulate the growth of new cartilage or blood vessels in the treatment of osteoarthritis and as the source of adult stem cells in other orthopedic surgical procedures such as the treatment of non-unions, osteonecrosis, bone grafts and spinal fusions.  We use comprehensive immune therapy or Applied BioLogics as adjunctive immune therapy applied pre and post transplant of the stem cells to control chronic inflammation.

The BioTherapy Research Institute, an operating division of the Stowe Foundation, uses the entire Applied BioLogics protocol and Autologous Blood Therapy to provide comprehensive Regenerative Medicine for chronic illness.  Every device and product used inside the boundaries of the Institute has FDA clearance.  The Institute simply applies the technology platform in a very precise order to achieve synergistic results.  The BioTherapy Research Institute currently operates a fee for service clinic in San Diego, CA called Stowe BioTherapy.  The clinic utilizes the proprietary technology of The Stowe Foundation to generate revenue through patient service fees.  In order to draw attention to the technology breakthrough, the Stowe Foundation helped Harvest Technology conduct two dramatic case histories of the BMAC system in the US.

Rafael Neiman, M.D., Orthopedic Trauma Surgeons of Northern California reported a case study in Feb 2007 where he injected adult stem cells derived from the BMAC system into a female patient's broken legs, which had not healed seven months post surgery, and achieved complete fracture closure and union.  Dr. Neiman treated his patient without open surgery by utilizing the BMAC system and the injection techniques pioneered by Dr. Hernigou in Europe for healing non-unions with bone marrow grafts.  Scott Spann, M.D., Orthopedic Spine Surgeon, Hospital at Westlake Medical Center in Austin, TX reports in May, 2006 that he implanted concentrated stem cells from the BMAC system into a female patient to accelerate a spine fusion and alleviate debilitating back pain.  The patient has reported in numerous public interviews the tremendous relief she has achieved in one treatment of BMC after 10 years of conventional treatment for her chronic back pain.  Harvest Technology has recently entered into discussions with a major orthopedic surgical supply company about licensing and distribution agreements on the BMAC system.

Carticel established the precedent of cartilage repair using human cell therapy in 1997.  The original Carticel product had to go through a rigorous FDA approval process as the autologous chondrocyte cells, used as the progenitor cells for cartilage repair, are more then minimally altered and manipulated through an extensive laboratory preparation process of the final cell product.  The preparation of the Carticel product occurs over several days and after a preliminary surgical procedure to harvest the initial cell population.  The final autologous progenitor cells are then blended in with growth factors and marketed as Carticel, the human cell therapy product used to achieve cartilage repair.  Its primary indication is to repair the cartilage that has broken down from repetitive trauma.  Surgeons have to be trained to use the Carticel protocol.

Recent news announcements have been made by Genzyme regarding the post marketing studies of Carticel.  The post marketing studies permit a more complete labeling of the product. Osteoarthritis is no longer an indicated use of the Carticel product.

The Genzyme cell therapy for cartilage repair is not a point of care service. The final cellular product to be used in the progenitor cell transplant has to be processed through a rigorous chain of command.  The cellular product is produced in Genzyme’s offsite molecular biology lab and the harvesting of the initial cells requires a surgical office visit and the transplant surgery itself is a hospital procedure.  However, the Genzyme protocol did establish the therapeutic benefit of human cell therapy for cartilage repair.  According to Genzyme, several thousand patients have been treated for knee repair.  The market is now open for competitive products and procedures.  Harvest Technology is a competitor to Genzyme.  They both supply FDA approved cell products for human cell therapy and cartilage repair.

The bone marrow concentrate produced by the Harvest Technology equipment is an autologous blood product that is cleared by the FDA as a source of adult stem cells for human cell therapy. The source of adult stem cells is called the bone marrow concentrate (BMC).  Harvest Technology is in the business of marketing their centrifuge as a medical device that can be placed in the operating room to instantly deliver FDA approved human cell therapy products.  The bone marrow concentrate is an autologous blood product that can be used in point of care service in any cell therapy procedure that has been approved by the FDA and in which the BMC has been demonstrated to be safe and effective.  Hence, Harvest Technology can compete against Genzyme in the business of cartilage repair using human cell therapy.  It is up to Harvest Technology to recruit the orthopedic surgeon to use the BMC product as opposed to the Carticel.

Other competitors to Genzyme are still in the process of getting their cellular products approved by the FDA.  Harvest Technology competes against the Biosurgery division of Genzyme to recruit orthopedic surgeons to use their product in a wide variety of orthopedic applications approved for human cell therapy.  The Stowe Foundation happens to own and control the information about cartilage repair in osteoarthritis as we paid Dr. Fortier at Cornell to do the large animal studies to prove the safety and efficacy of the BMC in the repair of cartilage.  The equine knee is the only large animal model approved by the FDA for the study of osteoarthritis.  The large animal studies established the safety and efficacy of the autologous blood product, the BMC produced by Harvest Technology in the repair of cartilage.  By definition autologous blood products are deemed safe for human use and several European study groups have used autologous bone marrow grafts in orthopedics since 1990.

Dr. Hernigou in Paris, France has used autologous bone marrow grafts in his private orthopedic surgery practice since 1990.  He published a review of his clinical practice in 2005 entitled, “The use of Percutaneous Autologous Bone Marrow Transplantation in Non-Union and Avascular Necrosis of Bone”.  By 2005 he had treated more then 1,000 patients with bone marrow transplants. He encountered minimal safety issues and established the proof of concept that bone marrow stem cells can deliver effective results.  This is roughly the same order of magnitude as patients who have been treated with Carticel.

Dr. Hernigou has also published two peer reviewed studies with 5 to 10 year follow-ups.  One study involved 116 patients entitled “Treatment of Osteonecrosis with Autologous Bone Marrow Grafting” and the second was a 60 patient study entitled “Percutaneous Autologous Bone Marrow Grafting for Non-Unions”.  In both cases the published results clearly demonstrated that the bone marrow aspirate had to be concentrated to deliver a therapeutic dose of stem cells to the area to be treated. In his early studies, Dr. Hernigou concentrated cells through a cell separation process that took several days of processing and occurred in a lab outside of the surgical suite.  Dr. Hernigou was able to measure the cell concentrations and establish criteria for what constitutes a therapeutic dose of cells (CD34+ stem cells, mononuclear cells, leukocytes, and fibroblast colony-forming units, CFU-F).

Dr. Gangji of Brussels, Belgium also published a review in 2005 entitled “Stem Cell Therapy for Osteonecrosis of the Femoral Head”.  Dr. Gangji studied 13 patients (18 hips) with stage I or II (without subchondral fracture) osteonecrosis (ON) of the femoral head in a controlled, double- blind trial.  The aetiological factors were corticoid steroid therapy and alcohol abuse. For two hips, the aetiological factor could not be determined.  The hips were allocated to a program of core decompression only (control group) or core decompression and bone marrow implantation of bone marrow mononuclear cells (bone marrow graft group).  The outcomes were safety, clinical symptoms and disease progression.

After a 24-month follow-up, there was a significant reduction in pain and in joint symptoms within the bone marrow graft group.  At 24 months, five of the eight hips in the control group had deteriorated to stage III (stage of the subchondral fracture), whereas only one of the ten hips in the bone marrow graft group had progressed to this stage.  Survival analysis showed a significant difference in the time to collapse between the two groups. Moreover, in the bone marrow graft group, the volume of the necrotic lesion decreased by 35% after 24 months.

Hernigou also reported the results of his 116 patient study (189 hips) treated with core decompression and bone marrow grafting.  The patients were followed up from 5 to 11 years, with a mean of 7 years. The aetiological factors were corticosteroids for 16% of the hips, alcohol abuse for 30%, sickle cell disease for 34%, organ transplantation for 11%, idiopathic for 5% and miscellaneous causes for 4%.  The outcomes were changes in clinical symptoms, progression in radiographic stages and the need for hip replacement.  Corticosteroid use and alcohol abuse are among the most widely recognized risk factors for ON among Caucasians.

When patients were treated before collapse (stage I and stage II), hip replacement was done in 9 of the 145 hips.  Total hip replacement was necessary in 25 hips among the 44 hips operated after collapse (stage III and IV).   The number of CFU-F was significantly lower in ON attributed to corticosteroid therapy, alcohol abuse, or organ transplantation than in patients with sickle cell disease.  Dr. Hernigou also concluded that the different number of transplanted progenitor cells had a major influence on the outcome of the hip.

The two formal studies on osteonecrosis by Dr. Gangji and Dr. Hernigou have shown the safety and efficacy of the implantation of concentrated bone marrow stem cells in the early stages of ON of the femoral head.  Patients who had the greater number of progenitor cells transplanted in their hips had better outcomes.  In Dr. Hernigou’s study of ON, patients were followed up from 5 to 10 years.  The outcome was determined by changes in the Harris hip score, by progression in radiographic stages, and by the need for hip replacement.  In Dr. Gangji’s study, follow-up was two years.  Both studies clearly demonstrated the safety and efficacy of bone marrow transplants in osteonecrosis.

In Dr. Hernigou’s formal study of bone marrow grafting for non-unions, 60 patients were involved.  Bone union was obtained in 53 of the patients and the concentrated bone marrow that had been injected into the non-unions of those patients contained concentrations of progenitor cells at levels > 1500 progenitors/cc and a total average of 54,963 +/- 17,431 progenitors.  The concentration (634 +/- 187 progenitors/cc) and the total number (19,324 +/- 6843) of progenitors injected into the non-union sites of the seven patients in whom bone union was not obtained were both significantly lower (p = 0.001 and p < 0.01) than those in the patients who obtained bone union.  The volume of the mineralized  callus measured at four months on the computerized tomography scans of the patients who had bone union ranged from 0.8 to 5.3 cc (mean, 3.1 cc). There was a positive correlation between the volume of mineralized callus at four months and the number (p = 0.04) and concentration (p = 0.01) of fibroblast colony-forming units in the graft (p = 0.04).

Based on the results obtained in Europe, The Stowe Foundation and Harvest Technology commissioned a study on the concentration and absolute number of progenitors found in the human bone marrow concentrate (the BMC) produced by the Harvest Technology BMAC system, the medical centrifuge for concentrating bone marrow aspirate.  These results are reported in the abstract prepared by The Stowe Foundation’s research associates Dr Sherwin Kevy and Dr. May Jacobson, Autologous Stem Cell Concentration at Point of Care.

Dr Kevy and Dr. Jacobson are both associated with Harvard’s medical school and the CBR Institute for Biomedical Research, now known as the Immune Disease Institute, http://idi.harvard.edu/  and are also consultants retained by Harvest Technology for interactions with the FDA.  The study of human bone marrow confirmed that the BMAC system can concentrate the bone marrow aspirate within 20 minutes and provide the progenitor cell numbers required by Dr. Hernigou via a point of care service.  Dr. Hernigou now uses the BMAC system in his clinical practice as the source of the progenitor cells for treating ON and Non-Unions using bone marrow grafts. The FDA went on to confirm that the bone marrow product produced by the BMAC system is an autologous blood product and is approved for use in the intra-operative production of mononuclear cell concentrate for human cell therapy.

In the meantime, we have obtained permission from the Minister of Health in Mexico to proceed with a more accelerated program of stem cell transplants using the autologous bone marrow concentrate.  Bone marrow derived stem cells are being used throughout Europe to develop protocols for cardiac care, MS therapy and reversing diabetes.  The BMC is simply a very attractive and convenient source of the stem cells.  Long term follow-up to the stand alone treatment model used in Europe and Asia is showing that stem cell transplants lead to initial recovery of organ function, but the effects begin to fade after 18 to 24 months.  The Stowe Foundation believes the temporary nature of the recovery is due to the presence of chronic inflammation.

We are the only stem cell organization that does pre and post adjunctive immune therapy to maximize patient outcomes.  Our pre and post care is called Applied BioLogics and is the signature concept of the Stowe Foundation for eliminating chronic inflammation.  The research associates of the Stowe Foundation have developed Applied BioLogics over the past 20 years.  Pre and post care of the patient with immune therapy and the use of the bone marrow concentrate from Harvest Technology as a point of care stem cell product will allow Stowe BioTherapy to establish itself as the premier center for Regenerative Medicine in orthopedics and sports medicine. Regenerative Medicine is the key to the rehab process.

The Stowe Foundation provides interested parties doing their due diligence on osteoarthritis, a paper titled; Microfracture Surgery for Cartilage Repair.  Here small holes are drilled into the bone opposite the injured knee cartilage and bone marrow is allowed to leak into the injured site to try to repair the cartilage. The paper on microfracture surgery describes the benefits and success rate of using autologous, but not concentrated bone marrow.  Using the microfracture surgery procedure, there is no assurance that the repair site has received a therapeutic dose of the bone marrow stem cells. Hence the surgical procedure has its limitations.

Without the use of Applied BioLogics to control inflammation in the surgical site, there is no way to insure a successful healing response will occur and hence the stem cells may fail to repair the cartilage.  The presence of chronic inflammation has prevented both Carticel and the microfracture surgery process from being a successful treatment for osteoarthritis.  The chronic inflammation simply breaks down the tissue repair soon after the stem cells initiate the growth of new tissue.  Applied BioLogics can reverse chronic inflammation and permit the natural healing process to move forward.  Doctors that practice integrated and personalized medicine are very receptive to the science of Applied BioLogics.  The Stowe Foundation interacts with all physicians and surgeons who are willing to try adjunctive immune therapy to maximize patient outcomes.

The BMC transplanted to the injured cartilage site during the microfracture surgery will dramatically increase the number of adult stem cells available for tissue regeneration and The Foundation’s technology platform of Applied BioLogics will help insure a complete and rapid healing response. The magnetic therapy, cold lasers and micro-current technology supplied by The Stowe Foundation are part of the energy medicine protocols associated with controlling the biologically active energy fields surrounding the tissue.  The energy devices themselves are class II medical devices approved by the FDA for pain control.  We use the biological response modifiers (BRM) derived from plant extracts and animal products to modulate the immune system and to help control the chronic inflammation and to promote a healing response. Hyaluronic acid carried into the joint through aloe vera gel and emu oil assists in lubricating the joint and rebuilding the cartilage. This combination of products is a natural competitor to Synvisc a second product promoted by Genzyme, http://www.synvisc.com.

The Harvest Technology equipment prepares a true autologous blood product in point of care service whereby the BMC can deliver a therapeutic dose of stem cells to the tissue. The device has been cleared by the FDA for this purpose. It has been used by Dr. Neiman in the US to repair non healing unions and by Dr. Spann to assist spinal fusion.  We proved in the equine project at Cornell and Dr. Lisa Fortier that the bone marrow concentrate can be used to grow new cartilage.  The equine knee is the only large animal model approved by the FDA for the study of osteoarthritis.

Having been cleared by the FDA as an autologous blood product, the bone marrow concentrate (BMC) can be used for human cell therapy, but only in therapies where the therapeutic benefits of human cell therapy have been approved by the FDA.  Cartilage repair using cell therapy has a proven therapeutic benefit as demonstrated by Genzyme and the microfracture surgery procedure uses autologous bone marrow stem cells as do many other orthopedic surgeries such as autologous bone grafts.  The BMC is an autologous blood product and can be used in any of these procedures.  The choice is up to the surgeon.

The centrifuge manufactured by Harvest technology is the only medical device certified by the FDA to produce an autologous blood product, the BMC, in point of care service. We can use the BMC as a source of stem cells for human cell therapy in any application where a therapeutic benefit has been established.  Human cell therapy has been approved in many orthopedic applications.  Dr. Hernigou clearly demonstrated the safety and efficacy of the BMC by Harvest Technology in non-unions and osteonecrosis.

Our equine study clearly demonstrated the ability of the BMC to grow new cartilage.  The BMC has been cleared as an autologous blood product.  Duke University is looking at their own source of the adult stem cells for treating osteoarthritis as coming from manipulated fat cells. The Duke process of producing the stem cells for human cell therapy will have to be highly scrutinized by the FDA just as the Genzyme product was put through an exhaustive regulatory approval process. However, we can move directly into the operating surgical suite as the medical device manufactured by Harvest Technology has FDA clearance as an intra-operative medical device.

Hence, instead of drilling holes into the bone marrow during microfracture surgery to leak some bone marrow stem cells to initiate cartilage repair, the surgeon can simply transplant a therapeutic dose of the bone marrow concentrate to the damaged cartilage to initiate the growth of new cartilage. We proved this with the large animal studies at Cornell in affiliation with Dr. Lisa Fortier, http://www.vet.cornell.edu/labs/fortier.  Her work was very well received at the International Cartilage Repair Society held in Warsaw Poland in September of 2007 and at the February 2009 annual conference of the American Academy of Orthopedic Surgeons held in Las Vegas.

FDA clearance has been obtained on the medical device, the BMAC system, as producing an autologous blood product that can be used in the intra-operative setting.  The intra-operative setting applies to medical conditions where human cell therapy has a proven therapeutic benefit.  It applies to cartilage repair, non-unions, osteonecrosis, bone grafts, sports injuries (tendons & ligaments) and spine fusions.  Our magnetic therapy and micro-current technology and cold lasers are used pre and post transplant to speed the healing process and to control pain.  These medical devices are also FDA approved. Several of the Stowe Foundation’s research associates were on the engineering development teams that the created the medical devices.  The research associates of The Stowe Foundation are also therapists at Stowe BioTherapy’s San Diego clinic.

Patients coming to Stowe BioTherapy for cartilage repair will also be treated pre and post transplant of the BMC with comprehensive immune therapy. The combination of Applied BioLogics for comprehensive immune therapy coupled with the healing powers of the adult stem cells in the BMC offers the best hope of conquering osteoarthritis.  The treatment of osteoarthritis is the center piece of the Center for Regenerative Medicine.