In this paper, we address the problem of 3D volume reconstruction from depth adjacent subvolumes (i.e., sets of image frames) acquired using a confocal laser scanning microscope (CLSM). Our goal is to align sub-volumes by estimating an optimal global image transformation which preserves morphological smoothness of medical structures (called features, e.g., blood vessels) inside of a reconstructed 3D volume. We approached the problem by learning morphological characteristics of structures inside of each sub-volume, i.e. centroid trajectories of features. Next, adjacent sub-volumes are aligned by fusing the morphological characteristics of structures using extrapolation or model fitting. Finally, a global sub-volume to subvolume transformation is computed based on the entire set of fused structures. The trajectory-based 3D volume reconstruction method described here is evaluated with a pair of consecutive physical sections using two evaluation metrics for morphological continu