Date

March 2008

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Biomedical Engineering

Institution

Oregon Health & Science University

Abstract

In this thesis, aminolevulinic acid, ALA, induced photodynamic therapy is explored as a possible treatment of both equine sarcoids and canine acanthomatous epulis. ALA is relatively inexpensive, can be applied locally (either topically or injected) or systemically and does not leave the patient photosensitive for extended periods of time. This is because ALA is converted into protoporphyrin IX, PpIX, which is made in the heme pathway. Since cells normally create this PpIX in smaller amounts than is used for a PDT treatment, the cells already are good at minimizing the photosensitivity from this drug. Currently sarcoids are the most common equine tumor. Unfortunately none of the methods to treat sarcoids are effective at treating these sarcoids. Some of the side effects of the current treatments can be scarring or a tumor can become aggravated and begin to grow rapidly afterwards making veterinarians hesitant to treat these tumors for fear of making them more aggressive. Acanthomatous epulis is a cancer in the canine mandible that is very aggressive and often progressing into the bone of the mandible. Under normal circumstances the animal has to have a pieces of the mandible removed if the cancer is not caught at an early stage. If it was possible to treat this tumor with another method other than surgical excision of the bone then this would be a great advantage to the afflicted animal. One portion of these photodynamic therapy treatments was to develop a optical method to measure the changes in the tissue, such as a change in the amount of blood in the local tissue volume. A diffuse optical reflectance spectrometer was assembled and calibrated using tissue phantoms. These tissue phantoms were created to simulate the absorption and scattering ranges of tissue. These phantoms have known spectral absorption coefficients, from india ink, and reduced scattering coefficients, from intralipid, all suspended in acrylimide gels. Properties of the tissue such as the absorption of the oxygen saturation, fraction of blood and the protoporphyrin IX and the scattering in the tissue can be monitored by an iterative function based on the root mean square error from the measured and predicted tissue reflectance program written in Matlab. The absorption coefficient range for these gels was from 0 to 6.5cm[negative ¹] and the reduced scattering coefficient varied from 1 to 28.3 cm[negative ¹]. By fitting for the original phantoms the measurements showed a variation ±0.68 cm[negative ¹] in the middle of our range and at the extremes up to ±2.2 cm[negative ¹]. But these two spectra, the absorption of india ink and the scattering coefficient, were so similar them for more unique spectra the accuracy is increased. Using this Matlab program the buildup of the concentration of the photosensitive drug, protoporphyrin IX, can be measured using its absorption at 635 nm. Other properties of the tissue that can be measured are the amount of blood, oxygenation of the blood and the scattering of the tissue. In this document, one canine afflicted with acanthomatous epulis and fourteen equine with sarcoids that have been treated with one or multiple photodynamic therapy treatments are reviewed. The minimum amount of PpIX and light in the local tissue volume for an effective treatment is dependent on the type of tissue that is treated. The photodynamic threshold dose found for the canine acanthomatous epulis tissue was 7:3(±0:7)×10[superscript 18] photons per gram of tissue. For equine sarcoid tissue, the photodynamic threshold dose ranged from 6 - 8 × 10[superscript 18] photons per gram of tissue. For most treatments, the treatment depth was about 2 mm. The extinction coefficient of PpIX at 635nm was found to measure in the tissue to be about 21.6mm[negative ¹]mM[negative ¹]. A component model describing the rates that ALA and PpIX build up and leave the local treatment tissue was used. In this model, ALA was applied to the surface of the tissue at a known concentration. After the ALA had converted to PpIX the absorption of the PpIX could be measured. This rate was found to be about 1.2e[negative ³] to 1.6 e[negative superscript 4] [hr negative ¹]. The rate that the PpIX was found to leave the tissue with no treatment light on was about 0.4 to 1.4 [hr negative ¹]. The rate that the PpIX was photobleach or converted to photoproducts was found to be about 0.1 [hr negative ¹]. For the canine acanthomatous epulis, the photodynamic treatment was not aggressive enough for this tissue type. The current treatment light will not treat deep enough into the tissue to treat the full extent of the tumor down to the bone. For equine sarcoids this treatment seems an effective method of maintenance since surgery is known to aggravate the tumors in to aggressive growth but in the combination with a PDT treatment the growth seems to be kept under control. Combined with surgery, aesthetic results that may last up to two years can be achieved. Once the sarcoid starts returning another photodynamic therapy treatment will be needed to keep the tumor under control and limiting the size. This combination of surgery and photodynamic therapy was very effective at treating an equine with a tumor over the eye where other methods of treatment may have lost the eye itself; the photodynamic therapy treatment with surgical excision gave back the use of the eye. In conclusion, ALA-induced photodynamic therapy is not the best method for curing such deeply penetrating tumors. Though ALA-induced photodynamic therapy is effect as a maintenance treatment for sarcoids and may be useful for other shallow aliments.

Identifier

doi:10.6083/M4Q52MKW

School

OGI School of Science and Engineering

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