Researchers from the University of São Paulo and international collaborators have proposed a conceptual update to the foundational principles of musculoskeletal regenerative medicine. In a narrative review published in Frontiers in Bioengineering and Biotechnology, the team introduces the Regenerative Hexagon, a framework that expands the classical regenerative triad of scaffold, cells, and growth factors. By incorporating three additional host-state domains, the model aims to explain the significant variability in clinical outcomes that cannot be accounted for by preparation parameters alone. This approach shifts the focus from the composition of the biological product to the physiological state of the patient receiving it.

The traditional triad has guided tissue engineering for over two decades, establishing the minimum conditions believed necessary for tissue regeneration. However, contemporary biology recognizes that host immunity, mechanics, and metabolism actively shape the repair process. The new framework retains the original three construct components while adding the Systemic Host Environment, Biomechanics and Mechanotransduction, and Cellular Energetics. These new pillars are visualized as a Regenerative Star, where six short diagonals connect non-adjacent vertices to form two interlocking triads. This geometry represents the interactions between the delivered construct and the receiving host, rather than a static configuration.

The Systemic Host Environment pillar encompasses the gut-joint axis, sleep patterns, medications, physical conditioning, metabolic status, and the pre-existing immune profile. Evidence indicates that dysbiosis and metabolic comorbidities establish a chronic low-grade meta-inflammation that affects cartilage and tendon independently of mechanical load. For instance, a systematic review found that specific bacterial genera were enriched in osteoarthritis patients, while elevated circulating lipopolysaccharide was associated with pro-inflammatory cytokine release. These systemic factors converge on shared effector axes, such as Toll-like receptor 4 signalling, which may modulate the local response to orthobiologic injections.

Sleep and circadian regulation represent another critical component of the host environment. Sleep disorders affect a substantial majority of patients with osteoarthritis and chronic pain, with prospective meta-analyses showing that baseline sleep problems predict incident and persistent chronic musculoskeletal pain. Experimental studies in healthy adults demonstrated that sleep fragmentation increases indices of peripheral and central sensitization and engages TLR4-stimulated monocyte production of inflammatory cytokines. Although sleep optimization is established as a treatment for sleep itself, its role as a modifier of orthobiologic response remains a hypothesis, particularly regarding its impact on pain-based trial endpoints.

The Biomechanics pillar addresses the mechanical environment and mechanotransduction, recognizing that articular cartilage is a mechanosensitive tissue. Chondrocytes sense compression and shear through various channels and transduce these signals to regulate matrix synthesis and inflammatory mediators. Loading follows an inverted U-curve, where physiological dynamic loading stimulates anabolic pathways, while excessive or absent loading activates catabolic cascades or leads to disuse atrophy. While structured exercise has high-quality evidence for reducing pain in knee osteoarthritis, the specific effect of correcting the mechanical environment on orthobiologic efficacy remains untested in randomized trials.

Cellular Energetics is defined as the energetic and redox state of resident and administered cells, which is closely linked to cell identity and differentiation. Oxidative stress impairs mitochondrial function and accelerates chondrocyte senescence, a central feature of osteoarthritis. Biophysical modalities such as pulsed radiofrequency, photobiomodulation, and pulsed electromagnetic fields are proposed to modify this state. Pulsed radiofrequency, in particular, has been studied for its neuromodulatory effects, including the suppression of calcitonin gene-related peptide and substance P release. The hypothesis is that these modalities may condition the microenvironment to potentiate the trophic signals supplied by orthobiologics, although clinical evidence for this combination remains preliminary.

A key insight from the framework is the preparation-dependent nature of host factors. In a comparative analysis of patients receiving platelet-rich plasma or microfragmented adipose tissue for knee osteoarthritis, higher body mass index was associated with inferior outcomes after microfragmented adipose tissue but not after platelet-rich plasma. This dissociation suggests that general health is not a global multiplier applied uniformly to all regenerative interventions. Instead, it interacts with the cellular and growth factor pillars in a preparation-specific manner, challenging the notion that the pillars contribute additively to the final outcome.

The authors hypothesize that the pillars interact multiplicatively rather than additively, a proposition that is not yet supported by a quantitative model. If the interaction is multiplicative, a major deficiency in one pillar may constrain the response achievable by optimizing another. This has significant implications for trial design, suggesting that factorial randomization is necessary to separate additive from interactive contributions. The framework reorients inquiry from asking which preparation is superior to asking in which host a given preparation performs, and why.

The Regenerative Hexagon is offered as a hypothesis-generating framework rather than a validated clinical instrument. It does not supplant the triad but makes explicit the host-level systems on which the triad depends. The evidence for each component is graded, with interactions demonstrated within a single experimental system separated from those inferred from separate literatures. Future prospective trials should systematically measure the status of all six pillars at baseline and correlate these profiles with clinical and structural outcomes. By specifying which interactions to test first, the framework aims to guide the development of precision regenerative medicine protocols in the coming decade.

Subject of Research: A narrative review proposing the Regenerative Hexagon framework to integrate host-state modifiers into musculoskeletal regenerative medicine.

Article Title: The regenerative hexagon: six domains shaping musculoskeletal regenerative outcomes

Article References: de Moraes Ferreira Jorge, D., Protásio Netto, J., de Andrade, R. M., Mosaner, T., Huber, S., Costa, F. R., Purita, J., Everts, P. A., & Lana, J. F. (2026). The regenerative hexagon: six domains shaping musculoskeletal regenerative outcomes. Frontiers in Bioengineering and Biotechnology, 14, Article 1986913. https://doi.org/10.3389/fbioe.2026.1986913

Image Credits: AI Generated

DOI: 10.3389/fbioe.2026.1986913

Keywords: regenerative medicine, orthobiologics, musculoskeletal, host immunity, biomechanics, cellular energetics, osteoarthritis, platelet-rich plasma, tissue engineering, clinical outcomes, regenerative, hexagon