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Translational Therapies for Type 2 Diabetes [Working Title]
Open access peer-reviewed chapter - ONLINE FIRST
Next-Generation Translational Therapies for Diabetic Foot Ulcers in Type 2 Diabetes: Integrating Smart Biomaterials, Nanomedicine and Regenerative Medicine
Written By
Seçil Nazife Parlak, Muhammet Volkan Bülbül and
Merve Nur Güney
Submitted: 14 July 2026Reviewed: 30 July 2026Published: 03 September 2026
Diabetic foot ulcers (DFUs) remain among the most disabling and costly complications of type 2 diabetes mellitus, driving the majority of non-traumatic lower-limb amputations and carrying a five-year mortality that rivals many aggressive cancers. Their refractory nature reflects a self-perpetuating pathological microenvironment in which hyperglycaemia, oxidative stress, advanced glycation end-product accumulation, immune senescence, sustained pro-inflammatory macrophage activation, impaired angiogenesis, and biofilm-forming, frequently drug-resistant infections converge to arrest the normal progression of wound repair. Conventional standard-of-care dressings and off-loading strategies address symptoms rather than these interlocking mechanisms and leave a large therapeutic gap. This chapter synthesises the most recent advances across three rapidly maturing and increasingly convergent domains of translational wound medicine: smart biomaterials, in particular stimuli-responsive, self-healing, conductive and sensing hydrogels engineered to actively remodel the wound micro-environment; nano-medicine, spanning metallic nanoparticles, metal-organic frameworks, catalytic nanozymes, electrospun nano-fibres, and phototherapeutic nano-platforms that deliver multi-modal anti-microbial and pro-regenerative activity; and regenerative medicine, encompassing mesenchymal stem cells, engineered exosomes, bio-engineered skin substitutes and three-dimensional bioprinting. Emphasis is placed on integrated next-generation platforms, including exosome-laden responsive hydrogels, glucose-oxidase-enabled photothermal micro-needles and closed-loop theranostic wearables that couple continuous biosensing with on-demand therapy. The mechanistic rationale linking each technology to a specific pathophysiological target is highlighted, and the principal barriers to clinical translation, including vascularisation, scalable manufacturing, standardisation, safety and reimbursement, are critically appraised. Together, these developments signal a paradigm shift from passive wound coverage towards precision, micro-environment-adaptive and personalised DFU therapeutics.
Department of Histology and Embryology, Faculty of Medicine, Ağrı İbrahim Çeçen University, Ağrı, Türkiye
Muhammet Volkan Bülbül
Department of Histology and Embryology, Faculty of Medicine, Ağrı, Türkiye
Merve Nur Güney
Department of Histology and Embryology, Faculty of Medicine, Ağrı, Türkiye
*Address all correspondence to: seeparlak@gmail.com
1. Introduction
Diabetes mellitus has become one of the defining chronic diseases of the twenty-first century. According to the International Diabetes Federation, approximately 589 million adults aged 20 to 79 years were living with diabetes in 2024, a figure projected to continue rising steeply over the coming decades, with type 2 diabetes accounting for the overwhelming majority of cases [1]. Among the many complications of sustained hyperglycaemia, the diabetic foot ulcer (DFU) stands out as one of the most feared, disabling, and economically burdensome. It is estimated that between 15% and 25% of people with diabetes will develop a foot ulcer during their lifetime, and global pooled analyses place the prevalence of DFU at around 6.3% of the diabetic population, with pronounced regional variation reaching roughly 13% in North America and lower figures across Asia and Europe [2, 3].
The clinical trajectory of a DFU is frequently unfavourable. These wounds precede the majority of non-traumatic lower-extremity amputations in people with diabetes, recur in up to two-thirds of patients within five years, and are associated with a five-year mortality that is comparable to that of several common malignancies [4, 5]. Beyond their impact on individual patients, DFUs impose an enormous and escalating burden on health systems, with national analyses documenting sustained rates of hospital admission for diabetes-related foot disease and lower-extremity amputation across the twenty-first century [6]. First-ever ulceration is driven by a constellation of risk factors including peripheral neuropathy, peripheral arterial disease, retinopathy, nephropathy, and reduced physical activity, underscoring the systemic and multifactorial nature of the disease [7].
For decades, the mainstays of DFU management have comprised glycaemic control, pressure off-loading, debridement, infection control, and moisture-retentive dressings [8]. While these measures remain essential, they are fundamentally supportive: they create conditions that permit healing but do not directly correct the deranged molecular and cellular biology that renders the diabetic wound chronic. A substantial proportion of ulcers consequently fail to close within accepted time frames, and many progress to infection and amputation despite optimal conventional care. This persistent therapeutic gap has catalysed intense research into technologies that actively re-engineer the wound micro-environment and re-store reparative capacity.
Particulary three fields have advanced rapidly and now stand at the forefront of translational wound medicine: smart biomaterials, nano-medicine, and regenerative medicine. Historically pursued in relative isolation, these disciplines are increasingly converging into integrated, multi-functional platforms that combine micro-environment sensing, on-demand drug release, potent anti-microbial action and cell or vesicle-based regeneration within a single construct. The central argument of this chapter is that the future of DFU therapy lies precisely in this convergence, mechanism-matched, adaptive and personalised, rather than in any single modality used in isolation.
This chapter is organised to reflect that thesis. Section 2 outlines the pathophysiological landscape of the type 2 diabetic wound, establishing the mechanistic targets that next-generation therapies aim to address. Sections 3–5 examine, in turn, smart biomaterials, nano-medicine, and regenerative medicine, emphasising the most recent developments and the specific pathological processes each technology engages. Section 6 focuses on the convergence of these fields into integrated theranostic and closed-loop platforms. Section 7 critically appraises the barriers to clinical translation and the regulatory and health-economic context, and Section 8 offers concluding perspectives and future directions. Because some readers will not be specialists in wound biology or biomaterials science, key concepts are introduced in accessible terms while retaining the depth expected of a specialist audience.
What distinguishes this chapter from existing reviews is its explicitly integrative framing. Rather than surveying smart biomaterials, nano-medicine, and regenerative medicine as separate fields, it maps each class of technology onto the specific pathophysiological defect it is designed to correct (Figure 1; Table 1) and argues that the decisive advances now emerging lie at their convergence – exosome-laden responsive hydrogels, glucose-oxidase-enabled photothermal micro-needles and closed-loop theranostic wearables. The accompanying comparative synthesis of evidence level, translational barrier and regulatory status across these emerging therapies (Table 5) is offered as an original contribution that situates each approach on a common translational map rather than in isolation.
2. Pathophysiological landscape of the type 2 diabetic wound
Cutaneous wound healing normally proceeds through overlapping phases of haemostasis, inflammation, proliferation and remodelling, orchestrated by a tightly regulated dialogue among immune cells, keratinocytes, fibroblasts, endothelial cells, and the extracellular matrix (ECM). In type 2 diabetes, this coordinated programme is derailed at nearly every stage, converting a self-limiting repair process into a chronic, non-healing state [9]. Understanding these derailments is essential because each represents a potential therapeutic target for the technologies discussed later in this chapter.
2.1 The hyperglycaemic and oxidative micro-environment
Sustained hyperglycaemia is the upstream driver of diabetic wound pathology. Elevated glucose promotes the non-enzymatic glycation of proteins and lipids, generating advanced glycation end-products (AGEs) that accumulate in wound tissue and interact with their receptor (RAGE) to amplify intracellular signalling. This drives excessive production of reactive oxygen species (ROS) and activation of the nuclear factor kappa-B (NF-κB) pathway, establishing a state of chronic oxidative stress and low-grade metabolic inflammation [10, 11]. Mitochondrial dysfunction compounds this picture: hyperglycaemia increases mitochondrial ROS generation in endothelial cells and fibroblasts, while impaired mitophagy allows damaged mitochondria to persist, leak mitochondrial DNA and further fuel inflammatory signalling in a self-reinforcing cycle [12]. The resulting redox imbalance damages cellular macro-molecules, impairs cell migration and proliferation, and pushes reparative cells towards senescence.
2.2 Immune dysregulation and the stalled inflammatory phase
A hallmark of the diabetic wound is failure to resolve inflammation. Under normal conditions, macrophages transition from a pro-inflammatory (classically activated, M1-like) phenotype during early repair to a pro-resolving, reparative (alternatively activated, M2-like) phenotype that supports proliferation and remodelling. In diabetes, this switch is impaired: hyperglycaemia, AGEs and ROS sustain M1-dominant polarisation, prolong the release of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-1 beta, and disrupt the growth-factor and angiogenic signalling required to progress to the proliferative phase [11, 13]. Paradoxically, the diabetic immune system also exhibits senescence and exhaustion: chronic activation blunts the acute response to injury, delaying immune-cell recruitment, impairing neutrophil function, and increasing susceptibility to infection [10]. Recent work frames these events within a metabolism-senescence axis, in which metabolic stress drives pre-mature senescence of fibroblasts, endothelial cells, and macrophages, and the resulting senescence-associated secretory phenotype perpetuates inflammation and inhibits repair [14].
2.3 Impaired angiogenesis and matrix dysregulation
Effective healing depends on the formation of new blood vessels to supply oxygen and nutrients to the regenerating tissue. Diabetic wounds are markedly hypoxic and angiogenesis-deficient. Endothelial dysfunction and reduced bio-availability of pro-angiogenic mediators such as, vascular endothelial growth factor and platelet-derived growth factor-BB impair the reciprocal endothelial-fibroblast signalling that normally drives neo-vascularisation and ECM deposition [12]. Concurrently, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors is disrupted in favour of excessive proteolysis, degrading the provisional matrix and growth factors faster than they can be replaced. Diabetic fibroblasts show reduced proliferative and migratory capacity and diminished collagen synthesis, further weakening the structural scaffold on which re-epithelialisation depends [9, 12]. The net effect is a wound bed that cannot build or sustain the granulation tissue needed for closure.
2.4 Infection, biofilm, and anti-microbial resistance
Infection is a major determinant of DFU progression and the single most important precipitant of amputation. Impaired immune surveillance, poor perfusion, and a nutrient-rich exudate render diabetic wounds highly susceptible to colonisation. Many chronic ulcers harbour structured, poly-microbial biofilms that shield resident bacteria from host defences and systemic anti-biotics, and the growing prevalence of multi-drug-resistant organisms further complicates management and worsens prognosis [15]. This confluence of infection, biofilm, and resistance provides a strong rationale for wound therapies that deliver potent, localised, and multi-modal anti-microbial action while avoiding the selective pressures associated with conventional systemic antibiotics. Taken together, the interlocking processes summarised in this section, hyperglycaemic oxidative stress, unresolved inflammation, angiogenic and matrix failure, and recalcitrant infection, define the mechanistic targets that next-generation smart biomaterials, nano-medicines, and regenerative therapies are designed to engage [16] (Figure 1; Table 1).
Figure 1.
Pathophysiology of the type-2 diabetic foot ulcer. Four interlocking pathological axes – hyperglycaemic/oxidative stress, immune dysregulation, angiogenic and matrix failure, and recalcitrant infection – converge to arrest wound repair and define the mechanistic targets addressed in Sections 3–6.
Smart, or stimulus-responsive, biomaterials are designed to sense and react to specific cues in their surroundings, changing their physico-chemical properties or releasing therapeutic cargo in response. Hydrogels, three-dimensional networks of hydrophilic polymers that retain large volumes of water, are especially well suited to wound care: they mimic the hydrated architecture of the native ECM, maintain a moist healing environment, conform to irregular wound geometries and can be loaded with a wide range of bioactive agents [17]. The transition from inert coverings to ‘intelligent’ dressings capable of dynamically adapting to the shifting diabetic wound micro-environment represents one of the most significant conceptual advances in the field [18]. The principal functional classes of these materials are summarised in Figure 2 and Table 2.
3.1 Stimuli-responsive hydrogels
Responsive hydrogels are classified according to the trigger to which they react. Endogenous triggers exploit pathological features intrinsic to the diabetic wound. Glucose-responsive systems, for example, incorporate glucose oxidase, phenylboronic acid moieties or glucose-binding elements so that elevated local glucose drives swelling, matrix reconfiguration or drug release; coupling glucose oxidase to the network additionally consumes glucose and can generate anti-microbial species in situ [17, 19]. Because chronic wounds are typically alkaline and rich in ROS, pH-responsive and ROS-responsive hydrogels have been engineered to release anti-inflammatory or anti-oxidant payloads selectively where the micro-environment is most hostile, simultaneously scavenging ROS and buffering the wound bed to more favourable conditions [18, 20]. Enzyme-responsive designs that react to the elevated MMP activity of chronic wounds provide a further layer of on-demand, pathology-gated delivery.
Exogenous triggers allow clinician or patient-directed control. Temperature-responsive polymers undergo sol-gel transitions that enable injectable, in-situ-forming dressings, while light-responsive and near-infrared-activated systems permit spatially and temporally precise release and drive localised photothermal anti-microbial effects [19, 21]. The most sophisticated constructs are multi-responsive, integrating two or more triggers so that the dressing can distinguish between different phases of healing and tailor its behaviour accordingly [21].
3.2 Self-healing, injectable, and adhesive systems
Diabetic foot wounds are subject to repeated mechanical stress from weight-bearing and movement, which can fracture a rigid dressing and expose the wound. Self-healing hydrogels, built from reversible dynamic bonds such as, Schiff bases, hydrogen bonding, host–guest interactions or metal–ligand coordination, autonomously repair structural damage and thereby maintain a continuous protective and therapeutic interface over the wound [22]. When combined with injectability, these materials can be delivered as a flowable precursor that gels in place to fill deep or irregular ulcer cavities, achieving intimate wound contact without surgical implantation. Strong tissue adhesion, wet-adhesive chemistries inspired by mussel-derived catechol groups being a prominent example, further ensures that the dressing remains in place, and it can also confer haemostatic benefit [17, 19]. Collectively, these mechanical innovations address the practical durability problems that have limited earlier dressings in the demanding environment of the diabetic foot.
3.3 Conductive and bioelectronic hydrogels
Endogenous electric fields are important in diabetes attenuated cue guiding cell migration during wound healing. Electrically conductive hydrogels, formulated with conductive polymers, carbon nanomaterials or metallic components, can restore and amplify these signals and serve as substrates for electrical-stimulation therapy that promotes cell proliferation, migration, and angiogenesis [20]. A notable recent direction is the development of self-powered systems: thermoelectric hydrogels that harvest the temperature gradient between the skin and the environment to generate therapeutic electrical stimulation without an external power source, thereby amplifying the wound’s own electric field and accelerating closure [20]. Such bioelectronic dressings blur the boundary between passive material and active medical device.
3.4 Sensing and theranostic dressings
The logical extension of the smart-material concept is the dressing that not only treats but also reports on the wound. Sensing hydrogels incorporate colourimetric, fluorescent, or electrochemical elements that respond to clinically meaningful parameters, most commonly pH, but also temperature, glucose, ROS or specific infection biomarkers, providing a visible or digitally readable indication of wound status without dressing removal [18]. By enabling continuous, non-disruptive monitoring, these smart-monitoring platforms can flag deterioration or infection early and, when integrated with responsive therapeutic release, form the material basis for the closed-loop theranostic systems discussed in Section 6 [18, 20].
Figure 2.
Smart biomaterials for diabetic wound healing. Four functional classes of intelligent hydrogel dressing – stimuli-responsive, self-healing/injectable/adhesive, conductive/bioelectronic, and sensing/theranostic – that sense and dynamically re-model the wound micro-environment.
4. Nano-medicine: Precision delivery and multi-modal anti-microbial action
Nano-medicine exploits the unique physico-chemical properties that emerge at the nanoscale, a high surface-area-to-volume ratio, tunable surface chemistry, and intrinsic catalytic or optical activity to achieve therapeutic effects that are difficult to obtain with bulk materials. In the context of DFU, nano-materials offer three particularly valuable capabilities: potent and localised anti-microbial action against resistant and biofilm-associated pathogens; catalytic modulation of the oxidative and inflammatory micro-environment; and efficient, protected delivery of labile biological cargoes [23]. These nanoscale agents are seldom used alone; they are most often incorporated into dressings, scaffolds or hydrogels, reinforcing the theme of convergence. Figure 3 and Table 3 summarise the main nano-medicine platforms and their mechanisms.
4.1 Metallic and metal-oxide nano-particles
Metallic and metal-oxide nano-particles are among the most extensively studied nano-materials for diabetic wounds, valued primarily for broad-spectrum anti-microbial activity that operates through mechanisms distinct from conventional anti-biotics, including membrane disruption, ion release and generation of ROS at the bacterial surface [23]. Silver nano-particles remain a benchmark anti-bacterial agent, while copper and zinc-based nano-particles combine anti-microbial action with pro-angiogenic and pro-proliferative effects relevant to tissue repair. Zinc oxide nano-particles synthesised by ‘green’, plant-extract-mediated routes and coated with chitosan, for instance, have been reported to promote diabetic wound healing while suppressing pro-inflammatory tumour necrosis factor-alpha and interleukin-6 and interleukin-1 beta signalling, illustrating how nano-particle design can couple anti-microbial and immunomodulatory functions [24]. Careful attention to dose, surface coating and biodegradation is required, however, because metal-based nanomaterials carry potential for cytotoxicity and environmental accumulation.
4.2 Metal-organic frameworks and catalytic nanozymes
Metal-organic frameworks (MOFs), highly porous crystalline hybrids of metal nodes and organic linkers, provide exceptional loading capacity and tunable, sustained release, and their gradual degradation can liberate therapeutic metal ions such as copper that both combat infection and stimulate angiogenesis [25]. A foundational example is the folic-acid-stabilised copper MOF nano-particle shown to improve diabetic wound healing, which helped establish MOFs as a versatile wound-therapeutic platform [25]. Complementing these are nanozymes, nano-materials with intrinsic enzyme-mimicking catalytic activity. Nanozymes with catalase – and superoxide-dismutase-like activity can catalytically scavenge the excess ROS that characterise the diabetic wound, while glucose-oxidase-based systems deplete local glucose to relieve hyperglycaemic cytotoxicity. When these catalytic functions are combined, for example a glucose-oxidase and polyoxometalate nanozyme system within a polysaccharide matrix, they can simultaneously lower glucose, neutralise ROS and reprogramme macrophages towards the reparative M2 phenotype, achieving near-complete wound closure with enhanced angiogenesis and collagen deposition in pre-clinical diabetic models [26].
4.3 Electrospun nano-fibres and nano-composite scaffolds
Electrospinning produces non-woven meshes of ultrafine fibres whose high porosity and large surface area closely resemble the fibrous architecture of native ECM, making them attractive wound scaffolds that support cell attachment and gas exchange [27]. Incorporating nano-particles, MOFs or natural therapeutic agents into electrospun fibres enhances drug-loading capacity and mitigates the burst-release problem common to other carriers, enabling sustained, localised delivery of anti-microbial, anti-oxidant and anti-inflammatory payloads. The MOF-loaded electrospun nano-fibre dressings that carry natural bioactive compounds exemplify this strategy, offering synergistic anti-inflammatory, anti-oxidant, and anti-bacterial activity from a single, ECM-mimetic construct [27]. Such nano-composite scaffolds also serve as effective delivery vehicles for cells and extracellular vesicles, linking nano-medicine to the regenerative approaches discussed below.
4.4 Phototherapeutic nano-platforms
Light-activated nano-therapies provide a non-antibiotic route to eradicating resistant and biofilm-associated infection. In photodynamic therapy, a photosensitiser is activated by light of a specific wavelength to generate cytotoxic ROS that kill adjacent micro-organisms, whereas photothermal therapy converts absorbed light into localised heat sufficient to ablate bacteria. Nanoscale constructs improve the delivery, stability, and selectivity of these treatments: chitosan-coated gold-silver core-shell nano-particles conjugated with a photosensitiser, for example, have demonstrated effective, non-toxic photodynamic killing of multi-drug-resistant mono and polymicrobial biofilms relevant to diabetic foot infection [28]. Because their anti-microbial effect is spatially confined to the illuminated wound and does not rely on conventional anti-biotic mechanisms, phototherapeutic nano-platforms are especially appealing for infections that are otherwise difficult to treat, and they integrate naturally with responsive hydrogels and microneedle systems.
Figure 3.
Nano-medicine platforms in DFU. Metallic and metal-oxide nano-particles, metal-organic frameworks and catalytic nanozymes, electrospun nano-fibres, and phototherapeutic nano-platforms provide precision delivery and multi-modal anti-microbial and pro-regenerative action.
Platform
Principal mechanism
Key effect
Refs.
Metallic/metal-oxide NPs (Ag, Cu, ZnO)
Membrane disruption, ion release, surface ROS generation
Whereas smart biomaterials and nano-medicines chiefly re-model the wound micro-environment, regenerative medicine seeks to replenish the cells, signals and structural templates that the diabetic wound can no longer supply. Its principal strategies, cell therapy, extracellular-vesicle therapy, and bioengineered tissue substitutes, act on multiple pathological axes at once, promoting angiogenesis, resolving inflammation, and restoring ECM and epithelial architecture [29] (Figure 4, Table 4).
5.1 Mesenchymal stem cell therapies
Mesenchymal stem cells (MSCs) are the most widely investigated cell type for chronic wounds owing to their capacity for multi-lineage differentiation and, more importantly, their potent paracrine and immunomodulatory activity. By secreting growth factors, cytokines, and extracellular vesicles, MSCs promote angiogenesis, dampen excessive inflammation, reduce oxidative damage and support ECM remodelling [30]. The commonly studied sources present distinct trade-offs: adipose-derived stem cells are readily harvested and well suited to autologous use; bone-marrow-derived MSCs have the longest clinical track record; umbilical-cord-derived and Wharton’s-jelly-derived MSCs offer low immunogenicity for allogeneic application; and induced pluripotent stem cells provide a customisable but genomically demanding option [30]. A recognised limitation of directly applied cells is their poor survival and engraftment in the hostile diabetic wound bed, which has shifted much attention towards their secreted products.
5.2 Exosomes and engineered extracellular vesicles
Exosomes are nanoscale extracellular vesicles that carry proteins, lipids, and nucleic acids and mediate intercellular communication. MSC-derived exosomes recapitulate much of the therapeutic benefit of their parent cells, targeting inflammation, angiogenesis, neuroprotection, infection control, and matrix remodelling, while avoiding the risks and logistical complexity of live-cell administration [29, 31]. Their cargo can also be engineered to enhance potency: loading adipose-stem-cell exosomes with a therapeutic micro-RNA (miR-21-5p), which has been shown to promote keratinocyte proliferation and migration through Wnt/β-catenin signalling and to accelerate re-epithelialisation, collagen remodelling, and angiogenesis in diabetic wounds [32]. Importantly, exosome therapy has begun to demonstrate clinical benefit. In a double-blind randomised controlled trial, weekly topical application of Wharton’s-jelly-derived MSC exosomes alongside standard of care produced a significantly higher rate of complete DFU healing than standard care alone, with a favourable safety profile, providing early clinical validation of this approach [33]. A frequent challenge, the rapid clearance and low retention of vesicles in the wound, is increasingly addressed by embedding exosomes within hydrogels or scaffolds for sustained, localised delivery, again illustrating the convergence of regenerative medicine with biomaterials engineering.
5.3 Bioengineered skin substitutes and three-dimensional bioprinting
Bioengineered skin substitutes aim to replace lost tissue and supply a living, bioactive template for repair. Several dermal and bi-layered products, including well-known commercial substitutes, have been approved and used for DFUs and can accelerate closure relative to conventional dressings; hyaluronic-acid-based constructs seeded with autologous fibroblasts, for instance, have improved healing rates in diabetic ulcers in controlled studies [34, 35]. A recognised limitation of many first-generation substitutes is that the delivered cells do not achieve durable engraftment, so much of the benefit derives from transient bioactive signalling rather than permanent tissue integration [34]. Three-dimensional bioprinting represents the next stage of this technology, depositing cell-laden bioinks in defined spatial arrangements to reconstruct the stratified architecture of skin, and even to incorporate appendages and vasculature in a patient-specific manner [36]. Early clinical proof-of-concept has been reported using bioprinted autologous adipose-derived material applied to DFUs [36, 37]. Nevertheless, insufficient vascularisation of printed constructs, together with standardisation and scalability challenges, continues to constrain routine clinical adoption [36].
5.4 Clinical translation status
Regenerative approaches occupy a spectrum of translational maturity. Selected skin substitutes are already in clinical use; MSC and, increasingly, exosome therapies are advancing through early and mid-phase clinical trials with encouraging safety and efficacy signals; and bioprinted personalised constructs remain largely at the proof-of-concept stage [30, 33, 37]. Across the field, the recurring priorities are to standardise cell and vesicle products, extend the retention and viability of the therapeutic agent within the wound, and generate rigorous, adequately powered randomised evidence to support broad clinical use. These themes recur in the discussion of translational barriers in Section 7.
Figure 4.
Regenerative-medicine approaches for DFU are arranged along a translational-maturity gradient, from clinically used skin substitutes through MSC and exosome therapies in trials to bioprinting at proof-of-concept.
The preceding sections deliberately separated three fields that are, in practice, increasingly inseparable. The diabetic wound is a multi-factorial problem, and mounting evidence indicates that constructs simultaneously addressing several pathological axes outperform single-function therapies. The defining trend of next-generation DFU therapy is therefore convergence: the assembly of smart biomaterials, nano-medicines, and regenerative agents into unified, multi-functional and often intelligent platforms. Figure 5 depicts such an integrated, closed-loop theranostic platform.
6.1 Multi-functional hybrid constructs
Hybrid systems co-locate complementary functions within a single dressing so that their effects reinforce one another. Representative examples integrate glucose-oxidase-loaded porous MOFs, photothermal nano-materials and anti-oxidant hydrogels to achieve synergistic bacterial killing, glucose depletion, ROS scavenging and accelerated collagen deposition, and neovascularisation in diabetic wound models [38]. Conductive polysaccharide hydrogels co-loaded with lignin-silver and quercetin-based nano-particles similarly combine skin-matching mechanics, synergistic anti-bacterial action, potent ROS scavenging and pH-responsive drug release in one construct [26]. Embedding exosomes or MSCs within responsive hydrogels or nano-fibre scaffolds adds a regenerative dimension while solving the retention problem that limits cell and vesicle-based therapies, marrying microenvironmental control to reparative signalling [27, 32].
6.2 Micr-oneedle theranostics and closed-loop systems
Micro-needle arrays, micron-scale projections that painlessly penetrate the outer skin barrier, have emerged as a uniquely versatile platform because they can both deliver therapeutics into the wound bed and sample interstitial fluid for sensing [39]. Dissolvable and bioinspired micro-needle patches have been engineered to co-deliver glucose-oxidase-loaded MOFs, photothermal agents, and anti-oxidant hydrogels for synergistic, stimulus-responsive diabetic wound therapy [40]. The most ambitious vision couples sensing and therapy in a closed loop: a wearable ‘sense-act’ system that continuously monitors wound or metabolic biomarkers and autonomously delivers a matched therapeutic dose in real time [39, 40]. Such theranostic micro-needle systems, integrating multi-plexed biomarker detection with on-demand delivery, embody the principle of precision, feedback-controlled wound care and represent a genuine paradigm shift from static dressings toward dynamic, self-regulating therapeutic devices [40].
6.3 Artificial intelligence and personalised wound care
Artificial intelligence (AI) is beginning to serve as the interpretive layer that renders truly adaptive sensor-rich platforms. By analysing continuous streams of data on parameters such as, pH, temperature, glucose, ROS, and infection markers, AI models can detect deterioration or infection earlier than periodic clinical inspection can and can guide dynamic adjustment of therapy [41]. Integrated with smart micro-needle and hydrogel systems, AI enables individualised, feedback-driven treatment regimens that adapt to the specific and evolving biology of each patient’s wound, moving DFU management decisively towards personalised medicine [41]. Realising this potential at scale will require robust, validated algorithms, interoperable devices, and careful attention to data governance.
Figure 5.
Integrated next-generation theranostic platform. A closed-loop ‘sense–decide–act’ architecture couples multi-plexed biosensing and AI interpretation with micro-needle-based, stimulus-responsive therapy for precision, personalised DFU care.
7. Translational barriers, safety, and health-economic considerations
Despite remarkable pre-clinical progress, the translation of these technologies into routine clinical practice faces substantial and shared obstacles, and a clear-eyed appraisal of them is essential to realising their widespread impact. Firstly, vascularisation remains a persistent bottleneck for engineered tissues and bioprinted constructs, whose inner regions can become hypoxic and necrotic without a functional micro-vascular network [36]. Secondly, scalable and reproducible manufacturing under good-manufacturing-practice conditions is difficult for complex multi-component constructs, cell products and exosome preparations, and issues of long-term stability, storage and shelf-life are frequently unresolved [38]. Thirdly, the field suffers from a lack of standardisation in cell and vesicle characterisation, nano-material dosing and outcome reporting that impedes comparison across studies and regulatory evaluation [36].
Safety considerations are equally critical. Metal-based nano-materials raise concerns regarding cytotoxicity, biodistribution, and environmental accumulation; cell therapies require monitoring for immunogenicity and, for pluripotent-cell-derived products, genomic stability; and every implanted or applied construct must demonstrate acceptable biocompatibility and biodegradation profiles [23, 30]. Rigorous, adequately powered randomised controlled trials with clinically meaningful endpoints remain comparatively scarce, and much of the evidence base still rests on small animal models whose predictive value for human chronic wounds is limited [30, 33].
Finally, the health-economic and regulatory environment strongly shapes real-world adoption. Advanced constructs are costly to develop and produce, and their uptake depends heavily on reimbursement policy; recent regulatory and coverage decisions affecting skin-substitute products illustrate how rapidly the economic context can shift and how sensitive clinical availability is to payer decisions. Because DFU disproportionately affects populations and regions with constrained health resources, ensuring that next-generation therapies are affordable, scalable, and equitably accessible is not a secondary concern but a central determinant of their public-health value. Addressing these intertwined scientific, safety, regulatory, and economic barriers in a coordinated way will determine whether the laboratory promise of these technologies is translated into measurable reductions in ulceration, amputation and mortality.
Notwithstanding the pre-clinical weighting of the field, several lines of genuinely clinical evidence already exist and are worth foregrounding. Bioengineered skin substitutes are approved and in routine use, having shown accelerated closure relative to conventional dressings in controlled comparisons [34, 35]. Cell therapy has advanced furthest in registered, adequately described trials: in a phase 2 multi-centre, double-blind, placebo-controlled study of intramuscular placenta-derived mesenchymal stromal-like cells (PDA-002), 159 adults with chronic DFU were randomised across three cell doses and placebo, and the lowest dose achieved complete index-ulcer closure in 38.5% of the peripheral-arterial-disease subgroup versus 22.6% with placebo, with closure sustained for a further four weeks and no treatment-related serious adverse events (ClinicalTrials.gov NCT02264288) [42]. The strongest signal for the cell-free approach comes from a randomised, double-blind trial of Wharton’s-jelly MSC-derived exosome gel (ClinicalTrials.gov NCT06812637), in which 110 patients with refractory DFU were allocated to exosome gel plus standard of care (n = 40), standard of care alone (n = 35), or vehicle plus standard of care (n = 35); treatment was applied weekly for four weeks with 16 weeks of follow-up, and 85 patients completed per-protocol assessment. Complete healing was achieved in 53 of 85 evaluable patients (62%) overall, with a significantly higher proportion in the exosome arm, and mean time to complete epithelialisation was six weeks (range four–eight) in the treated group versus 20 weeks (range 12–28) in controls; median ulcer area in the treated group fell from 6.0 cm2 at baseline to 4.0 cm2 at two weeks and 2.7 cm2 at four weeks. Wound infection occurred in 2 of 30 treated patients (6%) compared with 7 of 24 controls (29%), and no adverse event was attributed to the exosome product [33].
These data establish clinical proof-of-principle, but their limitations should be read alongside them. Both trials are modest in size and short in follow-up relative to the recurrence horizon of DFU; the exosome trial reports a baseline imbalance in ulcer area between arms (6.0 cm2 in the treated group versus 2.0 cm2 and 2.7 cm2 in the control and vehicle groups), which complicates direct comparison of healing rates, and the PDA-002 trial was terminated early for commercial rather than clinical reasons, so its subgroup finding requires prospective confirmation. Larger, adequately powered, multi-centre trials with standardised dosing, blinded wound assessment and durability endpoints beyond 12 months remain the decisive missing piece.
Table 5 summarises where each emerging class currently sits on the evidence spectrum, its dominant translational bottleneck and the associated safety and regulatory considerations. Read together, these entries make clear that the field is evidentially heterogeneous: smart biomaterials and most nano-medicine constructs remain confined to pre-clinical animal data, cell therapies have reached early to mid-phase trials, and only selected skin substitutes and, more recently, MSC-derived exosomes have generated approved-product or randomised-controlled-trial evidence, respectively.
Immunogenicity and genomic stability for iPSC-derived products
MSC-derived exosomes
Randomised controlled trial (n = 110)
Standardisation and wound retention
GMP characterisation and dosing standards
Bioengineered skin substitutes
Approved/RCT
Cost and durable engraftment
Strongly reimbursement-sensitive availability
3D bioprinting
Proof-of-concept
Vascularisation, scalability
Combined device–biologic regulatory pathway
Closed-loop AI theranostics
Early prototype
Algorithm validation and interoperability
Data governance and software-as-a-medical-device oversight
Table 5.
Comparative snapshot of emerging translational DFU therapies: clinical evidence, principal barrier, and safety/regulatory context.
The regulatory pathway is itself a determinant of translational speed. Many next-generation constructs are combination products that straddle the boundaries between medical device, drug and advanced-therapy medicinal product, and the AI-driven closed-loop systems additionally fall under evolving software-as-a-medical-device frameworks. This regulatory complexity, coupled with the reimbursement sensitivity illustrated by recent coverage decisions for skin-substitute products, means that demonstrable clinical and health-economic value, not pre-clinical novelty alone, will govern which of these technologies reaches routine diabetic-foot care.
The DFUs persist as a leading cause of disability, amputation, and premature death in people with type 2 diabetes, and the conventional standard of care, though indispensable, does not correct the underlying pathological biology of the chronic diabetic wound. This chapter has argued that the most promising path forward lies in mechanism-matched, next-generation therapies drawn from three rapidly advancing fields. Smart biomaterials actively remodel the wound micro-environment through stimulus-responsive, self-healing, conductive, and sensing hydrogels. Nano-medicine delivers multi-modal anti-microbial and pro-regenerative action through metallic nano-particles, MOFs, catalytic nanozymes, electrospun nano-fibres and phototherapeutic platforms. Regenerative medicine restores reparative capacity through MSCs, engineered exosomes, bioengineered skin substitutes, and three-dimensional bioprinting.
The unifying and most consequential theme is convergence. The diabetic wound is a multi-factorial disease, and integrated platforms, exosome-laden responsive hydrogels, glucose-oxidase-enabled photothermal micro-needles, and closed-loop AI-guided theranostic wearables, which engage several pathological axes simultaneously, are consistently more effective than single-modality approaches. These systems point towards a future of precision wound care in which therapy is adaptive, personalised, and responsive in real time to the biology of the individual ulcer.
Realising this vision will require concerted progress on vascularisation, scalable and standardised manufacturing, long-term safety, and rigorous clinical validation, together with health-economic and regulatory frameworks that make effective therapies affordable and equitably accessible. If these challenges are met, the convergence of smart biomaterials, nano-medicine, and regenerative medicine offers a credible route to transforming the DFU from a frequently limb and life-threatening complication into a reliably manageable and healable condition.
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