1. Reconstructing tissue, not just healing wounds
Regenerative medicine is evolving from symptomatic repair to functional biological restoration. Conventional wound treatments, while effective for achieving epithelial coverage, frequently result in the formation of fibrotic scar tissue that is functionally and aesthetically inferior to native skin and lacks critical appendages such as hair follicles and sweat glands [
1]. The absence of these structures leads to significant long-term morbidity, including impaired thermoregulation and reduced mechanical resilience. This deficit highlights a major unmet clinical challenge and is the primary driver for the paradigm shift from simple wound closure to functional tissue regeneration [
2].
Cell and gene therapies (CGTs) are transforming regenerative medicine through the integration of cellular, genetic, and material interventions. This engineering paradigm enables endogenous tissue regeneration and aims to recreate the developmental processes that generate skin
de novo. The central challenge is to engineer a local “regenerative niche” that overrides the default fibrotic healing pathway. This requires an engineering-driven framework focused on modulating the host’s own cellular and immune systems to achieve complete biological reconstruction. To visually summarize the core framework proposed from this perspective, a schematic diagram (
Fig. 1) has been added. The figure illustrates the interconnections among the five pillars—cellular engineering, gene therapy, smart biomaterials, advanced manufacturing, and adaptive regulatory science—highlighting their synergistic and feedback-driven relationships that collectively enable a closed-loop regenerative engineering system.
2. Representative research in China: A systems approach to regeneration
2.1. Stem cell-based wound repair and sweat gland regeneration
Chinese research groups have progressed from engineering simple cell delivery to engineering systems that actively instruct cell fate. Foundational work has established that mesenchymal stem cells (MSCs), when delivered to a wound site, can create a pro-regenerative microenvironment, moving beyond simple wound coverage to functional appendage restoration. Building on this, our team has focused extensively on the functional restoration of skin appendages, particularly sweat glands. Recent breakthroughs have involved the generation of sweat gland organoids (iSwGOs) from a patient’s autologous epidermal keratinocytes. By reprogramming these cells via the introduction of the developmental gene ectodysplasin A (
EDA) expression within a specialized three-dimensional (3D) culture system, we successfully engineered organoids that, upon transplantation, developed into fully functional, sweat-producing glands [
3]. This strategy represents a significant advance toward personalized regenerative therapy for complete skin restoration.
Furthermore, research into the paracrine mechanisms of MSCs has given rise to a promising “cell-free” therapeutic paradigm using MSC-secreted small extracellular vesicles (sEVs). This modality offers advantages in terms of safety, stability, and manufacturing scalability. Our team has advanced this concept by engineering sEVs to carry specific therapeutic cargo. For instance, in a study targeting diabetic wounds, we developed sEVs loaded with a specific circular RNA (circCDK13). When delivered locally, these engineered sEVs significantly accelerated wound closure and skin appendage regeneration in preclinical models [
4]. This progression from cell delivery to precisely engineered, cell-free biologics illustrates a core theme in regenerative engineering: the systematic deconstruction of biological function to create more precise and potent therapies.
2.2. Epidemiological profiling and clinical translation
A data-driven understanding of clinical needs is essential for translational research. Epidemiological analyses of inpatients in China with chronic wounds have identified diabetic foot ulcers as the predominant pathology, highlighting an urgent need for biologically active therapies. This powerful evidence of high prevalence and staggering costs was instrumental in shaping national health policy, culminating in the formal recognition of “wound repair” as a tertiary medical discipline in China [
5]. This move has catalyzed infrastructure development, standardized clinical training, and created dedicated talent pipelines to support the adoption of advanced regenerative interventions.
2.3. Bioactive scaffolds with controlled release systems
Recent progress has included the development of bionic scaffolds loaded with signaling modulators, such as glycogen synthase kinase-3 (GSK-3) inhibitors (e.g., SB216763), to promote angiogenesis and hair follicle neogenesis. These smart materials not only act as passive carriers but also actively modulate the wound microenvironment to improve regenerative outcomes [
6]. This concept of the scaffold as an active signaling platform extends to other classes of materials. A more sophisticated approach involves harnessing mechanotransduction, for which the physical properties of the scaffold are engineered to direct cell fate. For instance, mechano-active nanocomposite hydrogels that can dissipate stress at the wound site, promoting healing in mobile areas such as joints, have been developed [
7]. Collectively, the results of these studies trace a clear trajectory—from the development of simple carriers to that of artificial extracellular matrices that deliver chemical, ionic, and mechanical cues to guide cells toward functional tissue reconstruction.
2.4. Wound microenvironment engineering
The future of cell-based therapies lies in engineering cells that can autonomously sense and respond to their environment. Using synthetic biology, cells can be engineered with gene circuits that respond to local stimuli such as hypoxia or inflammatory cytokines. These “programmable cells” function as biological machines, executing logical functions to deliver a tailored therapeutic response. For example, a circuit might sense high levels of inflammatory cytokines and, in response, actuate the expression of an anti-inflammatory protein [
8].
Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology serves as a cornerstone in this approach. In a representative study, CRISPR/Cas9 was used to knock out
Ndrg2 gene expression in dendritic cells, enhancing their intrinsic proregenerative capabilities. These edited cells, encapsulated in a hydrogel, significantly accelerated healing and vascularization in preclinical models [
9]. This synergy between gene editing, cell therapy, and biomaterial delivery systems exemplifies the push toward creating “intelligent cell” therapy—an autonomous, implantable “microdoctor” capable of executing complex, personalized treatment protocols.
3. Innovation in CGT engineering: Core technologies and manufacturing
3.1. Viral and nonviral gene delivery
Innovative delivery vehicles are critical for enabling CGTs. Adeno-associated viruses (AAVs) and lipid nanoparticles (LNPs) have emerged as two leading platforms for in vivo gene therapy. AAVs are prized for mediating long-term gene expression but are limited by a small packaging capacity and potential immunogenicity. In contrast, LNPs, validated in coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines, are a nonviral platform that offers a greater payload capacity, has low intrinsic immunogenicity, allows for repeated dosing, and features a more scalable manufacturing process.
For cutaneous applications, a primary challenge is surmounting the stratum corneum. Vyjuvek™, a topical gene therapy approved by the US Food and Drug Administration (FDA) in 2023, established a landmark regulatory precedent for this route of administration [
10]. Following this, research has intensified on the use of LNPs to deliver gene-editing tools to the skin. Recent studies have demonstrated that LNP formulations can efficiently deliver Cas9 as mRNA or a ribonucleoprotein complex for
in situ gene editing in human skin models, highlighting the potential of this “hit-and-run” strategy for developing permanent cures for monogenic skin diseases [
11].
3.2. Smart biomaterials for functional skin regeneration
The role of biomaterials has evolved far beyond providing passive structural support, and they now function as active biological interfaces that modulate critical regenerative processes. This has driven the engineering of “smart” or “stimulus-responsive” biomaterials that transform wound dressings into therapeutic systems. These materials can sense and respond to cues within the wound microenvironment, such as changes in pH or reactive oxygen species (ROS) levels, allowing for the on-demand release of therapeutic agents. For example, multiresponsive hydrogels have been developed that react to a combination of pH, ROS, and glucose levels while incorporating photothermal agents that can be activated by external light to enhance antibacterial effects [
12]. In a representative study, compared with conventional hydrogel controls, a ROS/pH dual-responsive hydrogel achieved a 70% reduction in bacterial load and a 1.8-fold acceleration of re-epithelialization, quantitatively demonstrating the benefit of microenvironment-adaptive design.
Beyond responsive release, the material’s intrinsic structure can be engineered to be therapeutic. Our team’s recent work on programmable regeneration-directing artificial skin (RDAS) exemplifies this [
13]. The system uses a multilayered hydrogel built with DNA components to create a highly organized matrix that mimics the natural dermis. This preprogrammed structure provides powerful instructive cues to resident cells, guiding fibroblasts toward a regenerative phenotype and preventing scar formation without exogenous cells or growth factors. These examples illustrate a paradigm in which the material is not just a container but an integral, intelligent component of the therapy itself.
3.3. Good manufacturing practice (GMP)-compliant manufacturing and artificial intelligence (AI) integration
A major bottleneck in clinical translation is manufacturing. Traditional cell therapy production is often an open, manual process, resulting in high costs and variability. The engineering solution is a shift toward automated, closed-loop, and integrated manufacturing platforms, or “GMP-in-a-box” systems. These platforms integrate multiple unit operations—cell sorting, activation, transduction, and expansion—into a single, automated workflow, reducing manual labor and contamination risk while enabling scalable production [
14]. In recent pilot facilities, these “GMP-in-a-box” systems reduced operator time by approximately 60% and batch-to-batch variability by more than 30%, confirming their suitability for large-scale CGT manufacturing.
Furthermore, AI is enhancing these systems. AI algorithms can analyze real-time data from integrated sensors—monitoring cell morphology, viability, and metabolic rates—to predict culture outcomes and trigger automated adjustments, ensuring product quality and consistency [
15]. This engineering-driven industrialization is essential for transforming CGTs from niche treatments into standardized, accessible medicines.
4. Regulation, ethics, and the Chinese industrial ecosystem
The successful translation of CGT innovations is critically dependent on a supportive and adaptive regulatory and industrial ecosystem. The regulatory environment in China is rapidly evolving to support CGT innovation, with accelerated pathways and conditional approvals being implemented to facilitate development [
16]. The formal establishment of wound repair as a national tertiary medical specialty was another critical step, spurring the development of specialized clinical departments and standardized training programs. Globally, regulatory agencies are also evolving toward the adaptive oversight of CGTs. The FDA established the regenerative medicine advanced therapy (RMAT) designation to accelerate clinical translation, while the European Medicines Agency (EMA) implemented adaptive licensing pathways for conditional approval. In China, the National Medical Products Administration (NMPA) released the
Guideline for clinical translation of cell and gene therapies in 2023, introducing conditional approval and real-world evidence tracking systems. This convergence of global and national policies underscores a shared emphasis on balancing innovation with patient safety and long-term ethical governance.
However, this rapid technological advancement has brought significant ethical considerations to the forefront. Ethical frameworks focused on gene editing and data governance remain critical areas for improvement. With respect to gene editing, concerns extend beyond technical issues such as off-target effects to the profound societal questions surrounding long-term safety and the internationally recognized prohibition of germline modification. Furthermore, as manufacturing and diagnostics become increasingly reliant on AI, the governance of patient data has become a complex ethical frontier, raising issues of privacy, security, and ownership. Establishing clear guidelines for informed consent and the equitable use of data-driven insights is essential for ensuring public trust and guiding the responsible development of these powerful technologies.
5. Toward an integrated regenerative engineering system
While tissue engineering and regenerative medicine focus primarily on biological reconstruction through cells, scaffolds, and growth factors, regenerative engineering—as proposed by Esdaille et al. [
17] and Laurencin and Khan [
18]—is a broader, convergence-based discipline that unites materials science, stem cell biology, developmental biology, and clinical translation into a single transdisciplinary framework. This distinction reframes regenerative practice from component-based repair to systems-level engineering, which forms the conceptual foundation of the five-pillar framework presented herein. To maximize the clinical potential of CGT, China is advancing a multidimensional platform that integrates key technological pillars into a cohesive, engineered system. This vision moves beyond isolated breakthroughs to a systems-level approach through which innovations are combined to create therapies with unprecedented efficacy. We propose a five-dimensional integrated platform that synergizes the key pillars of modern regenerative medicine. The power of regenerative engineering lies in its convergence—the deliberate fusion of disparate technological domains to create emergent capabilities. For example, the combination of smart biomaterials with programmable gene circuits enables
in situ control of cellular behavior, and AI-enabled manufacturing links bench-scale design directly to clinical-grade production. Such integration exemplifies the regenerative engineering paradigm—a dynamic ecosystem in which biology, materials, and computation coevolve toward self-sustaining tissue regeneration (
Table 1).
• Cellular engineering: This moves beyond primary stem cells to encompass highly defined and controllable sources, such as induced pluripotent stem cells (iPSCs), and “programmable” cells modified with synthetic gene circuits to sense and respond to pathological signals.
• Gene therapy: This provides molecular tools for cellular engineering, leveraging advanced gene-editing technologies such as CRISPR/Cas9 and state-of-the-art delivery systems, particularly nonviral LNPs, for both ex vivo manufacturing and direct in vivo administration.
• Smart biomaterials: This provides the essential physical and signaling microenvironment, involving responsive hydrogels and bioactive scaffolds that communicate with cells through a combination of chemical, ionic, and mechanical cues to promote regeneration over fibrosis.
• Manufacturing systems: This is the critical enabling pillar, focusing on automated, closed-loop, and GMP-compliant platforms controlled by AI and real-time analytics to produce complex CGT products at scale and with high consistency.
• Regulatory science: This provides a framework for oversight and evaluation, including adaptive regulatory pathways that can accelerate the approval of promising therapies and the use of real-world evidence to monitor long-term safety and effectiveness.
This integrated system elevates regenerative practices from isolated therapies to cohesive, engineered platforms. The final product is the output of a fully integrated, end-to-end engineering pipeline, representing a fundamental shift from a component-focused approach to a true system engineering paradigm for regenerative medicine.
6. Conclusion
China’s five-pillar framework—cellular engineering, gene therapy, smart biomaterials, advanced manufacturing, and adaptive regulatory science—marks a shift from isolated advances to a system engineering paradigm. By embracing the convergence principles of regenerative engineering, future work should focus on standardization, ethical governance, and industrial scalability to translate these innovations into globally competitive living medicines.
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