The regenerative hexagon: six domains shaping musculoskeletal regenerative outcomes

The classical regenerative triad of scaffold, cells, and growth factors has guided musculoskeletal regenerative medicine for over two decades, yet outcome variability after orthobiologic treatment is not explained by preparation parameters alone. Contemporary regenerative biology already recognizes that host immunity, mechanics, and metabolism shape repair; what is less developed is a framework that integrates these dimensions for orthobiologic treatment and states their interactions in testable form. We propose an update of the triad concept rather than a replacement of it: a Regenerative Hexagon that retains the three construct components and adds three host-state domains that modify the response to them. These are the Systemic Host Environment, encompassing the gut-joint axis, sleep, medications, conditioning, metabolic status, and the pre-existing immune profile; Biomechanics and Mechanotransduction; and Cellular Energetics, defined as the energetic and redox state of resident and administered cells, which biophysical modalities are proposed to modify. Six short diagonals connect non-adjacent vertices, forming two interlocking triads that generate the Regenerative Star, and the framework is read as a sequence of states across the phases of repair rather than as a static configuration. The evidence for each component is graded with explicit criteria, and interactions demonstrated within a single experimental system are separated from those inferred from separate literatures. Convergent mechanisms are proposed: sleep fragmentation in healthy volunteers and dysbiosis-derived endotoxin in mechanistic studies both engage Toll-like receptor 4 signalling, and host metabolic burden was associated with orthobiologic response in a preparation-dependent manner. We hypothesize that the pillars interact multiplicatively rather than additively, a proposition not yet supported by a quantitative model and testable in factorial trials. The Regenerative Star is offered as a hypothesis-generating framework rather than a validated clinical instrument, reorienting inquiry from which preparation is superior toward in which host a given preparation performs.