Regenerative Medicine Healing Thy Self

Regenerative Medicine

Healing Thy Self Still Requires Faith, but Less So

The trachea is an essential structure connecting the lungs to the mouth and being born without one is fatal 99% of the time (Sifferlin). Hannah Warren, a Korean Canadian, was unlucky enough to face this fate and had been kept alive through a tube acting as an artificial trachea for the past two years. On April 9 of this year, Dr. Paolo Macchiarini at the Advanced Center for Translational Regenerative Medicine, Karolinska Institute in Stockholm, Sweden harvested stem cells from Hannah's bone marrow and seeded them into a trachea-shaped plastic mesh. The purpose of this surgery was to generate a trachea from Hannah's own cells.

This was the sixth such surgery ever performed and the first in the United States (Sifferlin). The FDA approval was based on the experimental nature of the surgery, which is typically allowed in cases when the patient's life is at risk. In other words, this type of surgery is considered a last resort because it has a low chance of success, but without it the patient will certainly die. The experimental nature of this research is evident from the different opinions expressed by regenerative medicine experts in Sifferlin's article, who conveyed the sense that the outcomes of these surgical interventions cannot be reliably predicted.

Despite the skepticism regarding the use of an artificial matrix scaffold for seeding autologous stem cells during a regenerative surgical intervention, the empirical research supporting this approach continues to expand (reviewed by Polzer et al.). One of the main advantages of this approach is the use of the patient's own cells, which should prevent an immune reaction against the regenerating tissue. Tissue rejections are not uncommon in more traditional non-autologous tissue transplant patients and powerful immune suppressing drugs are typically required to protect the transplanted tissue from the host's immune system. More traditional regenerative approaches have relied on taking tissue from other parts of the body, such as bone or skin, followed by grafting these tissues into the diseased or injured location. The problem with this approach is that the donor graft site is injured in the process. The use of stem cells to generate new autologous tissue avoids this problem.

During the early days of surgical intervention using artificial scaffolds seeded with stem cells it was discovered that the survivability of the cells was very low (Polzer 1). This was due to a lack of oxygen and other nutrients normally supplied by blood vessels. What was needed, therefore, was a prevascularized artificial scaffold that could support the newly transplanted cells. Polzer and colleagues investigated the various approaches to supporting cell survival during regenerative stem cell surgery in rodents. Although the researchers found in vitro seeding to be the most efficient, grafting a seeded scaffold into the body necessarily exposes the cells to hypoxic conditions until the scaffold become vascularized (Polzer 7). Most cells in hypoxic conditions will secrete angiogenic factors, including hypoxia-inducible factor 1-? (HIF-1?) and vascular endothelial growth factor (VEGF), which should help the scaffold become vascularized. How long this process takes and whether it will prevent the loss of seeded cells probably depends to a significant extent on the surrounding tissue and therefore represents another unknown.

HIF-1? And VEGF are also involved in osteogenesis, so the influence of these growth factors on the differentiation choices being made by the seeded stem cells is unknown (Polzer 7). The impact of prolonged hypoxic conditions on the seeded cells is another. Although Polzer and colleagues examined the timing of cell seeding relative to prevascularization, they discovered that the artificial scaffold rapidly filled with connective tissue. This process effectively clogged the matrix and prevented efficient seeding.

By comparison, researchers conducting spinal cord injury research into the efficacy of regenerative medicine techniques have been producing promising results (Sykova et al. 1113-1114). Hydrogels seeded with mesenchymal stem cells or bone marrow stem cells have produced positive results in both animal models and in phase I/II clinical trials. In rodents, the lesions were smaller 35 days post surgery and were functionally advanced compared to controls. White matter in the spinal cord was more intact and axons had begun to invade the scaffold from both ends of the transection. While most of seeded cells produced connective tissue, as the scaffold was being degraded by macrophages it was being replaced by additional connective and vascular tissue, astrocytic processes, and NF-160 positive axons. Functionally, patients who undertook the regenerative medicine intervention appeared to suffer no ill effects and may be doing better than they would have without the surgical intervention.