A blueprint for translational regenerative medicine

Abstract

The past few decades have produced a large number of proof-of-concept studies in regenerative medicine. However, the route to clinical adoption is fraught with technical and translational obstacles that frequently consign promising academic solutions to the so-called "valley of death." Here, we present a proposed blueprint for translational regenerative medicine. We offer principles to help guide the selection of cells and materials, present key in vivo imaging modalities, and argue that the host immune response should be considered throughout design and development. Last, we suggest a pathway to navigate the often complex regulatory and manufacturing landscape of translational regenerative medicine.

Figure 1

Overview of some common strategies, components and interactions used in regenerative medicine. Cells, biomaterials and biomolecules exhibit a number of interdependent interactions that can be exploited for various regenerative medicine strategies, including tissue engineering, drug delivery, immunomodulation and genetic engineering.

Figure 2

The host immune response and regenerative medicine. (A) Direct allorecognition occurs by cytotoxic T cells (Tc cells) recognizing and eliminating allogeneic donor cells, while indirect allorecognition occurs by helper T cells (Th cells) recognizing donor antigens taken up and displayed by host antigen-presenting cells. (B) Implanted biomaterials can provoke a foreign body reaction resulting in the formation of a fibrous capsule containing both macrophages and foreign body giant (FBG) cells. (C) An example of immune evasion, in which transgene expression and CRISPR/Cas9 are used to generate hypoimmunogenic hiPSCs with upregulated CD47 but neither class of MHC (B2m^-/- and Ciita^-/-). (D) An example of immune modulation, in which ECM-derived biomaterials recruit T helper 2 cells (Th2 cells), which secrete cytokines that can polarize macrophages to an M2-like phenotype. In turn, these alternatively-activated macrophages secrete cytokines that sustain Th2 cell activation.

Figure 3

Bench-to-bedside translation of regenerative medicine products. Translating an academic concept into a clinical product can be divided into three key stages: early research and development, pre-clinical product development and clinical studies. This schematic predominantly focuses on the technical aspects that should be considered by scientists at early technology readiness level (TRL), with higher TRL items included for context. Highlighted are the key tasks (yellow boxes), systematic quality control to fulfill all applicable requirements (blue boxes) and critical checkpoints that should be met throughout product translation (orange boxes), with each stage guided by experts in the field. The timeline of this schematic should not be considered an absolute scale, indeed, the relative time and work required at the different stages will vary considerably depending on the product or therapy that is being translated. It should also be noted that in the EU, good manufacturing practice (GMP) is applicable for medicines and ATMPs but not for medical devices.