To achieve long-term attachment of capsule endoscopes (CEs) and miniature biosensors in the human gastrointestinal (GI) tract, a tissue attachment mechanism (TAM) was designed, optimized and tested for safety and adhesive capabilities on excised tissue in vitro and in vivo on a live pig model. Six TAMs were tested for their attachment strength in an in vitro attachment tensile experiment in which each TAM was tested on three different proximal intestine tissue samples. The maximum strength and average value are 8.09 N and 4.54 N respectively. The initial attachment damage was tested for 10 min using a sine wave pull force on the TAM with a 0.4 N peak value and 6 s period, which represents typical human intestinal traction force from peristalsis. The in vitro attachment tensile test verified that the tissue was not visually damaged nor perforated by the attachment process. In the in vivo experiment, four TAMs were placed in the intestine of a pig through individual longitudinal enterotomies. X-ray images were taken each hour after the surgery and showed zero migration of the TAMs after 24 h of adhesion. X-ray images taken each day indicated the attachment duration of this mechanism lasted up to 6 days. Post experiment inspection confirmed the attachment did not cause visible damage to tissue. These results confirmed the reliability of the TAM in vivo and demonstrated preliminary feasibility of long-term sensor adhesion to the GI tract.