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Jan 1, 2009 (Vol. 29, No. 1)

Stem Cells Continue March Toward Clinic

New Methodologies and Technologies Abound in Both Quality and Quantity

  • Improving Cell Harvesting

    Stem cells are traditionally isolated from bone marrow by a chemical process called Ficoll density gradient separation, which precipitates the cells out and takes anywhere from 8–24 hours.

    Harvest Technologies has developed a system, BMAC™, that provides at least twice the number of total nucleated cells over the Ficoll process, says Gary Tureski, president. “Our technology provides a simple point-of-care procedure for concentrating these cells in about 15 minutes.”

    This process also eliminates culturing cells. “You have challenges when you culture because you don’t know if the culturing—which is accelerating cell division at an unnatural rate—is causing a problem or the culture medium is causing problems,” adds Kevin Benoit, vp and GM of strategic development.

    The FDA has granted IDE approval for a 48-patient feasibility study in the U.S. using BMAC to treat patients with end-stage critical limb ischemia. Patients will be injected with their own stem cells, processed by the company’s system, into the affected limb, in an attempt to prevent amputation.

    BMAC is also being used in Europe in several cardiac procedures. It is infused into coronary arteries, post-myocardial infarction, to repair a portion of heart damage, injected into heart muscle as adjunctive treatment with bypass surgery to improve heart function, and used in combination with laser cardiac procedures.

    The company has submitted an investigation device exemption for a double-blind placebo cardiac safety study—to inject BMAC cells into the myocardium during bypass surgery in patients with severely compromised heart function. It is expecting a favorable response by the FDA to start the study by the end of 2008, according to Tureski.

  • Synthetic Scaffold for 3-D Cell Culture

    Click Image To Enlarge +
    Adult mouse neural stem cell embedded in 3DM’s peptide scaffold product, Puramatrix, a synthetic hydrogel peptide that serves as a 3-D extracellular matrix, and supports the maintenance of stem cell phenotypes

    A synthetic peptide hydrogel discovered by Shuguang Zhang at MIT in 1992, now serves as a 3-D extracellular matrix cell culture. 3DM holds the exclusive license to the technology and has partnered with BD Biosciences to commercialize the BD Puramatrix™ research product. The firm is also developing the material for clinical applications in regenerative medicine.

    Puramatrix is a peptide (16 amino acid residues) that self-assembles to form a nano-fiber structure or hydrogel in aqueous solution. The strength of the scaffold can be adjusted for specific cell types, with the ability to deliver and release therapeutic proteins and stem cells in a localized area.

    Since it is fully synthetic and devoid of animal-derived materials, there is no risk of infection. It is also highly reproducible, yet also customizable—other cells and factors can be added to it. The nano-fiber structure resembles natural collagen; enabling cell proliferation equal to that within collagen.

    “As opposed to growing cells on just plastic, cells in a Puramatrix culture typically behave more like they would in normal tissue,” says Lisa Spirio, Ph.D., CTO and cofounder.

    She adds that it works well with stem cells, and the company has in vitro and in vivo data showing that Puramatrix supports maintenance of stem cell phenotypes, as well as differentiating stem cells into various cells of interest. The company is actively collaborating with various orthopedic, cardiac, and drug companies.

    Wound healing and dental bone clinical trials are expected to begin in early 2009 (first set of trials will not include stem cells). “It’s likely that these applications will require separate FDA approval,” Dr. Spirio says.

  • Cell-Based Product Manufacturing

    Click Image To Enlarge +
    Tissue Genesis’ TG1 1000 cell isolation system

    Some of the challenges companies face with stem cells, according to Alan Smith, Ph.D., CEO and president of Cognate Bioservices, include having adequate facilities, appropriate cleanrooms, and processes that can be scaled-up and manufactured under GMP.

    “We also find people looking for help with regard to developing appropriate quality control release testing and information on what the FDA is looking for in this area. I think a lot of people, especially small companies, don’t have a comprehensive understanding of good manufacturing practice and what that entails.” Dr. Smith adds that his company helps identify suitable reagents that are compatible with GMP and helps with receipt and testing of raw materials.

    In addition, it provides stem cell services, including development of cell-based therapeutics using bone marrow cells for tissue repair and regeneration. He explains that there are differences in processing stem cells based on their source. Bone-marrow-derived stem cells are typically in single cells in suspension versus adipose stem cells, which are tissue-based.

    “Working out those to optimize yields in manufacturing is often time consuming and critical because the cost of goods for the product is dependent on the number of stem cells one can derive from the starting material.”

    Additional challenges in regards to stem cells include reliability and robustness of the process to yield consistent outcomes. To address this, the company breaks the operation down into segments: procurement, shipping/logistics, manufacturing, scale-up, and quality control, said Dr. Smith.

    “We try to build in fail-safes to each of those aspects in addition to the quality control of the product that’s in tandem to the manufacturing process.” He adds that the firm has developed some techniques that allow for certain aspects of the stem cell process to occur in a closed-system fashion. The company is currently expanding its stem cell capabilities, including additional types of stem cells such as cord blood.

    Although the promise of stem cell therapy started with the first successful bone marrow transplants in 1968, it is just beginning to reach the clinic. Thanks to companies’ success in developing new technologies and methods of isolating, growing, and producing adult stems cells, their quality and quantity is increasing. There still remain many hurdles—such as regulatory and financial—before they can be used to treat patients. Yet, many companies remain optimistic that working together with the FDA will create a standard of quality that will help move the field from the bench to the bedside.

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