Regenerative medicine and emerging chronic pain management techniques (Proceedings)

The emerging field of Regenerative Medicine has many definitions; however the NIH's definition, "A treatment in which stem cells are induced to differentiate into the specific cell type required to repair damaged or destroyed cell populations or tissues." provides a basis for further discussion of stem cell therapies and their role in daily practice . Regenerative medicine was originally focused on tissue engineering and in vitro growth of replacement organs for transplant. However it has expanded to include other uses including the management of pain and chronic disease.

Using the term "stem cells" can elicit emotional responses from people depending on their understanding of the technology and their political and religious orientation. The most controversial stem cell type used for research has been embryonic stem cells. Originally it was believed that embryo's would be the only source of stem cells but further research demonstrated there are numerous sources of viable stem cells including bone marrow, blood vessels, muscle, and adipose tissue. The source of stem cells can alter the potential of the cells to differentiate and ultimately their use. For example, early embryonic cells are usually thought to be totipotent, meaning they can differentiate into almost any type of cell. Adult somatic cells tend to be multipotent meaning they can differentiate into more than one cell type, but only specific cell types in the series of cells derived from the original line (Table 1.) These adult cell types are often referred to by their source (e.g., hematopoietic stem cells, neural stem cells, epidermal stem cells, mesenchymal stem cells, etc.). Interestingly, hematopoietic stem cell therapy has been widely used in human medicine since the 1960's in the form of bone marrow transplant. It is bone marrow and adipose derived mesenchymal stem cells (MSC) which are of current interest to the clinician for the management of pain and orthopedic injury in veterinary medicine.

Table 1

The use of MSCs for the management of veterinary orthopedic disease was first commercially successful for tendon injuries in horses . They have since been increasingly used for the treatment of osteoarthritis in canine and equine patients. Bone marrow derived mesenchymal stem cells are also being investigated for use in many diseases in veterinary species. The autologus stem cells used for treatment of these conditions are of mesenchymal origin (usually adipose tissue) and seem to be effective by modifying injury healing and altering the local cytokine environment rather than by simply replacing diseased tissue and reversing the anatomy of degenerative tissue with pristine tissue .

Regulatory Considerations for Stem Cell Therapy

Veterinary pharmaceutical therapies are regulated by the FDA-Center for Veterinary Medicine. Cellular and tissue-based treatments are under the authority of the USDA-Center for Veterinary Biologics. Currently neither agency has chosen to regulate veterinary stem cell treatment . This is because current therapies do not exceed regulatory threshold due to minimal processing of autologus cells. However, if future therapies require involved engineering, culturing and cellular processing, the USDA, the FDA, or both may exert their authority and regulate the use of stem cells for therapeutic purposes.

Stem cells are not regulated by the US government and therefore have not received regulatory evaluation for safety or effectiveness. This probably means the use of stem cells should be viewed as an alternative or complementary therapy and thus veterinarians are unlikely to be prosecuted under the Food, Drug, and Cosmetic Act. However, veterinarians should be very careful to obtain informed consent from owners and carefully explain the known benefits, risks, costs, and alternatives to the proposed therapy . Future events and discoveries may alter the way the US government and state veterinary boards choose to classify stem cell therapies so veterinarians need to remain current on their understanding of regulatory requirements.

Cytokine Targeted Therapy

Cytokines play an important role in the destructive, inflammatory, and repair processes that occur during arthritis. In fact most of our current pharmacological treatment of pain is aimed at modifying the levels of prostaglandins in and around damaged tissue through the use of NSAIDs. Many basic experiments have been performed to identify and characterize the role that individual cytokines play in arthritis in people and veterinary species. While it is intriguing to contemplate a "silver bullet" that would nullify the role of a particular cytokine in inflammation while sparing all other constitutive cytokines, it appears that the disturbance of the balance of agonist and antagonistic actions at a multitude of receptors for many diverse cytokines is responsible for pain and inflammation. Effective therapies will probably alter multiple cytokine actions. However, the use of relatively specific targeted therapies may modify the tissue response to injury in a beneficial way and may play a role in the management of arthritis.

Autologous Conditioned Serum

Commercially available autologous blood processing systems are available for use in veterinary species. The underlying biological principal is the production of autologous cytokine receptor antagonists from the incubation of the patient's blood with immunocyte-stimulating substances. One target is interleukin-1 receptors. Interleukin-1 receptor antagonist (IL-1Ra) protein can be produced through the aseptic incubation of whole blood with glass beads ). After the prescribed time the serum can be separated and injected into the effected joint, increasing the concentration of autologous IL-1Ra in the synovial fluid and altering cellular responses to inflammatory signaling through interleukin-1. The advantages of this technology are the specific targeting of therapy and the use of autologous serum reducing the risk of adverse immune-mediated responses. The main disadvantage is risk of sepsis from contamination during processing.

Autologous Conditioned Plasma

Similar to autologous conditioned serum, autologous conditioned plasma is a patient-specific therapy which is mediated by growth factors produced by platelets. The main actions of these growth factors are reportedly proliferation and differentiation of stem cells, osteoblasts, and epidermal cells, enhanced production of interstitial and connective tissue constituents, increased angiogenesis, and increased chemotaxis . The growth factors responsible for these actions are listed in Table 2.

Table 2

Pamidronate for Palliative Therapy of Canine Appendicular Osteosarcoma

Bisphosphonates are a class of osteoclast inhibitors which reduce bone destruction associated with primary or metastatic bone neoplasia. The reduction in bone destruction should lead to an improvement of cancer-associated pain and bone destruction leading to improved quality of life. The limited amount of published clinical research indicates that bisphonsphonate therapy along with NSAID therapy improves pain relief and quality of life in approximately 25-40% of canine OSA patients .

NK-1 Receptor Ablation and Antagonists

Substance P has been long known to mediate nociception and the development of hyperalgesia in some models of chronic pain. Neurokinin-1 (NK-1) receptors located in the central nervous system can be selectively blocked with a new class of available antiemetic drugs known as NK-1 receptor antagonists (e.g., aprepitant and maropitant). It has been speculated that there may be a useful clinical effect of these drugs on the development of hyperalgesia or treatment of acute pain. However, clinical trials have not supported their role as analgesic drugs although they continue to be very useful as antiemetics .

Substance P conjugated to the receptor toxin, saporin, has been investigated as a tool for "molecular neurosurgery." By selectively destroying NK-1 receptors in the dorsal horn of the spinal cord by intrathecal administration of this conjugate, it was hypothesized central hypersensitization could be prevented or treated. Preliminary investigations into the safety of intrathecal administration in dogs demonstrated that it was reasonably safe

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