Make regeneration great again; stronger together

Regenerative therapies hold the potential of disrupting the healthcare and socioeconomic burden imposed by chronic disease. By targeting restoration of organ health, regenerative technologies are poised to transform clinical practice. Cardiovascular indications account for a quarter of cell-based regenerative products in development. Yet, in the clinical setting mixed outcomes have challenged practice adoption and subdued enthusiasm. Resurgence in regenerative medicine requires clinical development plans that ensure uniformity in therapeutic output, while enabling innovation that offers affordable regenerative solutions. The concept of stemness inherent to stem cell biology sparked the regenerative medicine revolution—aspiring to attain tissue repair or even one day achieve organ replacement. Underscoring the promise ahead, care providers and patients alike have referred to regenerative interventions as ‘courts of last resort’ to combat otherwise incurable chronic diseases. In the beginning, stem cells were envisioned as building blocks, capable to cobblestone together to create new tissue and ultimately fix a broken heart. Propelled by rapid transition from bench to man, pioneering efforts in cardiovascular regeneration established robust foundations for harvest, processing and delivery of cells, from the patient’s own body or from a donor source. However, the nature of cardiovascular disease mandates large numbers of patients and prolonged follow-up of hard end-points before efficacy can be validated, and therapeutic utility ultimately declared. Thus, despite decade-long efforts that have documented reassuring feasibility and safety, irrefutable evidence for cell-based benefit in the setting of a chronic cardiovascular condition has remained conspicuously elusive, typically associated with resounding benefit in few and modest to no benefit in most. The fact that only rare individuals, within cell-treated cohorts, appear to respond with a pronounced cardio-regenerative aptitude is becoming increasingly ostensible. This growing clinical experience informs the evolution of discovery and development strategies, including the next iteration of trials that implement evidence-based rigor for optimized delivery and targeted patient selection. Introduction of regenerative medicine options across communities of practice—within and beyond cardiovascular specialties—has remarkably accelerated knowledge acquisition, and consolidated a stronger grasp of organ repair principles. Shared experiences and in-depth (pre)clinical exploration have led to the realization that, although delivered stem cells are rapidly cleared at the site of delivery, regenerative impact is more sustained. Instead of the anticipated brick-and-mortar role in organ health restitution, stem cells may rather perpetuate endogenous healing processes through paracrine influence, but only within a permissive disease niche. Thus, the brute force of direct cell-mediate regeneration that was envisioned with stem cells as construction blocks may in reality hinge on a delicate balance between cellular regenerative potency and a tissue microenvironment amenable to its influence. Cross-correlation of clinical performance with molecular signatures of effective versus non-effective stem cell populations now allows for intelligent biotherapy design aimed to zoom-in on ensuring regenerative proficiency. In this context, systematic decoding of biological underpinnings supporting successful regeneration enables a shift away from generic biologics whose efficacy pivots on serendipity, and illuminates a path towards increasingly consistent outcome. The true era of enlightenment in regenerative medicine will come when biologics-based cues that provide curative influence can be matched to a substrate, amenable to reparative reconditioning. The notion that stem cell benefit is predicated upon a paracrine impact, underpins resurgence in interest and new science in the field. Discovery efforts are now rapidly moving past a ‘stem cell-only’ perspective for regenerative medicine to ones that embrace in unison science materials, protein chemistry, structural biology, and gene therapy. These complementary perspectives add value to the armamentarium of a field that initially was so focused on cell-centric platforms to catapult regenerative medicine from an unidimensional effort towards a multidisciplinary paradigm. Engineered technologies that can harbour the paracrine power of cell-mediated repair, while maintaining the capacity for scalable manufacturing provide a new path towards achieving cost control, uniform regenerative function, augmented patient safety, and a straight forward regulatory path. Furthermore, a lack of reliance on cell-based repair provides further ability to render technologies capable to achieve repair in tissue microenvironments more hostile to regenerative interventions. In this way, clinical therapies tailored to those with repair-permissive disease substrate can be rapidly initiated, while further work to develop novel technologies in resistant disease is pursued. In the end, the regenerative medicine model of care moves the current pattern of practice away from one that fights against disease towards one that perpetuates healing from within, to protect against chronic disease. Regenerative biotechnology offers the prospect of unprecedented solutions for many global health challenges. Adoption of a growing regenerative armamentarium into mainstream practice is projected to fuel 10% of the overall economic healthcare output within a decade. This emerging ‘bioeconomy’, fostered by public/private initiatives, is evolving to expedite timely and regimented incorporation of new biotherapies into the core healthcare portfolio. To address the needs of a rapidly aging and vulnerable population, the aspirational goal is to match increasing lifespan with healthspan in a cost-effective manner. Within a 2030 horizon, affordable access to proven regenerative therapies will be paramount in ensuring equitable coverage for at-risk populations. A unique opportunity in this space is the prospect of off-the-shelf and point-of-care technologies. These platforms provide the ability for two-to-three orders of magnitude scale-up in biomanufacturing to mitigate variability in function and assure quality. This is in contrast to the current state-of-the-art, where often single cell doses are manufactured and released at high cost. The burden of cost-intense cell manufacturing can be mitigated if the knowhow and biology carried forward from the stem cell era is translated into acellular alternatives aiming to provide consistent therapeutic performance, at low cost, for treated populations. Thus, clinical grade regenerative biotechnology must remain open to ongoing adaptation and continuous improvement in order to overcome technological limitations identified in early prototypes. In this context, aligning incentives for developing health therapies, including early reimbursement, with public health goals can serve as a catalyst to expedite transition into a regenerative model of care without disrupting current healthcare systems. The multidimensional fabric of regenerative medicine is intrinsic to the success of this emerging discipline. A unified public/private endeavour, that encompasses a holistic view of regenerative science, while accounting for population/patient diversity and practicality of practice application, will augment ultimate success. Thus, the path to making regeneration great again will be realized through a shared vision of strength together.