Small animal research allows detailed study of biological processes, disease progression and response to therapy with the potential to provide a natural bridge to the clinical environment. The Small Animal Radiation Research Platform (SARRP) is a novel and complete system capable of delivering multidirectional (focal), kilo-voltage radiation fields to targets in small animals under robotic control using cone-beam CT (CBCT) image guidance. The capability of the SARRP to deliver highly focused beams to multiple animal models provides new research opportunities that more realistically translate laboratory research to clinical treatment.

This thesis provides a complete overview of the SARRP and its calibration and radiation delivery capabilities. After reviewing the mechanical and control structure of the SARRP, the thesis focuses on the geometric calibration of the system for high-precision irradiation. A novel technique for the calibration of the treatment beam is presented, which employs an x-ray camera whose precise position need not be known. Using the camera system, we acquired a digitally reconstructed 3D "star shot" for gantry calibration and then developed a technique to align each beam to a common isocenter with the robotic animal positioning stages.

The thesis follows with development of different radiation delivery procedures. These methods enable the system to radiate through a series of points, representative of a complex shape. Pencil beam dose painting aims to target the tumor as accurately as possible and gives it the highest dose of radiation while sparing normal tissue as much as possible. For the first time, a particularly interesting case of shell dose irradiation is addressed. The goal in peripheral dose distribution is to deliver a high dose of radiation to the shape surface, with minimal dose to the shape interior. This goal is achieved by geometrically creating a spherical shell through intersecting cylinders in the SARRP configuration. The ability to deliver a dose shell allows mechanistic research of how a tumor interacts with its microenvironment to sustain its growth and lead to its resistance or recurrence.

In summary, SARRP is an image guided small animal radiotherapy system that addresses the significant technological disparity between traditional laboratory irradiation and clinical methods. It also enables new research directions, such as the study of tumors in their micro-environment. Development of this system required novel methods for accurate calibration and dose shell delivery, which are described in this thesis.