Nanotechnology 

Nanotechnology has unlocked a new generation of hydrogels that can be tuned for specific clinical demands. From degradation kinetics to drug release and mechanical resilience, nanoscale control is transforming hydrogels from passive wound dressings into active, minimally invasive platforms for joint restoration, tissue regeneration and targeted therapeutics

Jorg Schelfhout at Allegro

Hydrogels, known for their high water content and tissue-like properties, have traditionally been restricted to biomedical applications with a low mechanical load, such as wound dressings. Advances in nanotechnology now make it possible to transform these soft materials into mechanically robust and functionally versatile systems. By engineering polymer networks at the nanoscale – through controlled incorporation of particles, fibres, pores and crosslinkers – developers can tune critical parameters with a great degree of precision, including resistance under physiological strain, degradation kinetics aligned with tissue healing and programmable release of therapeutic agents.

A notable example is the design of injectable nano-enabled hydrogel microparticles for osteoarthritis treatment. These microgels assemble into a cohesive, shock-absorbing matrix capable of withstanding the high compressive and shear stresses typical of synovial joints, outperforming conventional bulk hydrogels in both mechanical resilience and biological performance. The same nanoscale design principles are applicable across a wide range of indications, from tissue scaffolds and cell delivery to adaptive drug-release platforms. What are some fundamental design strategies, performance trade-offs and translational pathways driving the next generation of nano-engineered hydrogels as multifunctional biomaterials.

From ‘wet sponges’ to recision soft matter

Classical hydrogels earned clinical trust because they are biocompatible, highly hydrated and diffusion-friendly. Yet, these very traits limited their use in dynamic, high-load settings. Conventional bulk gels: shear, tear or creep; they release drugs poorly under mechanical stress; and their degradation can be too slow for acute therapies or too fast for structural roles. Nanotechnology addresses these shortcomings by structuring soft matter at the 1-100nm scale and then building upward. Nanoscale elements – nanoparticles, nanofibres and molecularly precise crosslinkers – serve as ‘mechanical pixels’ that collectively determine macroscopic performance. Crucially, these elements can be combined modularly, so a single platform can be reformulated for very different clinical tasks without having to reinvent the chemistry each time. This is how nanotechnology allows precise control over mechanical behaviour, degradation rate, and drug release through nanoscale structuring and chemistry.

The modular tuning toolkit

Mechanically, next-generation hydrogels can be tuned to meet the stress of physiological environments by integrating nanomaterials that link molecular interactions with macroscopic performance. Nanofillers such as silica, clay platelets and graphene derivatives create sacrificial bonds that dissipate energy and prevent crack propagation, while supramolecular nanostructures – based on host-guest complexes, ionic nanodomains or hydrogen-bonded clusters – introduce crosslinks for better performance. Hybrid and double-network architectures combine nanoscale and microscale crosslinking to balance stiffness and flexibility. Similarly, nano-engineered microgel particles can form a continuous, viscoelastic matrix whose nanoscale interfaces control adhesion, friction and shock absorbance. Together, these strategies provide the mechanical resilience and adaptability needed for load-bearing biological applications.

Temporal control over degradation is equally important, ensuring that a hydrogel’s lifespan aligns with biological processes, lasting weeks for cartilage repair, days for post-operative pain relief or hours for local anaesthesia. This can be achieved through nanoscale chemical design, such as hydrolytically labile linkers (esters, orthoesters) for predictable erosion, enzyme-cleavable motifs like matrix metalloproteinases-sensitive peptides that couple degradation to tissue remodelling, and stimuli-responsive bonds (redox, light or chemical) for on-demand clearance or activation.

Finally, programmable drug release can be realised through nano-architectural control of the gel network. Embedding core-shell nanoparticles enables multistage delivery – combining an initial burst with sustained release – while affinity-based systems using heparin-mimetics or cyclodextrins buffer drug concentration and extend therapeutic availability. Mechanopharmacological designs add another level of control, with mechano-responsive pores that open under mechanical load to synchronise drug delivery with patient movement, such as ambulation-triggered analgesic dosing in joint or muscle applications.

Together, these nanotechnology-based strategies form a flexible design toolkit, enabling hydrogels to be tailored precisely to their mechanical, temporal and therapeutic requirements across diverse clinical contexts.

Case study: osteoarthritis and the synovial joint

The knee represents one of the most demanding environments for any biomaterial, exposed to compressive forces exceeding three to five times body weight, rapid shear rates and a chemically active synovial milieu. Conventional hyaluronic acid injections can temporarily restore viscosity, but their molecular entanglements are not designed to withstand repeated high mechanical strain. Bulk hydrogels face similar limitations; they are usually delivered as thick, viscous materials that are easily damaged by shear forces and tend to crack or break under stress. When this happens, the whole structure often fails at once.

A more effective approach is the microgel strategy; designing the hydrogel as injectable microparticles, typically 10-100µm in diameter, that can pass through a standard needle. This architecture offers several advantages. It enables minimally invasive delivery suitable for outpatient procedures, while the granular mechanics of the packed microgel absorbs shocks and maintains lubrication through interstitial fluid. The system’s extensive internal surface area provides ample sites for drug adsorption, or cell anchoring.

By tuning pores, size distribution and interparticle bonding, developers can incorporate functional payloads, such as anti-inflammatory agents or cues that promote chondrocyte stability and matrix renewal. Because the platform is modular, it can be reformulated for different joints, disease stages or therapeutic goals by tuning density, degradation kinetics and surface chemistry, illustrating how nanotechnology enables precise, condition-specific hydrogel design.

Safety, standards and the path to clinic

In Europe, the regulatory landscape for advanced biomaterials and combination products has been redefined by the Medical Device Regulation (MDR) (EU) 2017/745, which replaced the Medical Device Directive. The new regulation imposes more rigorous and transparent requirements for demonstrating safety, clinical performance and product traceability throughout the entire life cycle. For hydrogel-based systems – especially those used in load-bearing or drug-delivery applications – compliance now requires detailed evidence of mechanical reliability, biocompatibility and stability under physiologically relevant conditions. Under the MDR, hydrogels are classified according to their intended use, level of invasiveness and duration of body contact – criteria that can elevate their risk category compared with previous frameworks. This affects both the conformity assessment route and the extent of clinical evidence required. Manufacturers must demonstrate proven clinical benefit supported by their own data, and maintain post-market clinical follow-up programmes to monitor long-term safety and performance.

Comprehensive testing is now expected to include mechanical fatigue and degradation studies, chemical characterisation of leachables and degradation by-products, and toxicological risk assessments aligned with ISO 10993 standards.

For hydrogels incorporating nanoparticles or biologically active agents, additional scrutiny is applied under MDR Annex I, which addresses nanomaterial safety, tissue interaction and potential systemic exposure. Sterilisation validation – whether by gamma, e-beam or ethylene oxide – must confirm that the process preserves polymer network integrity and does not alter release behaviour or mechanical strength.

The MDR encourages an integrated, interdisciplinary approach combining elements of medical device regulation with pharmaceutical quality frameworks such as ICH Q8-Q10. Aligning materials science, toxicology, clinical design, manufacturing and quality control from the earliest development stages helps ensure consistent performance and regulatory readiness. Companies that adopt this proactive approach to MDR compliance can streamline approvals, minimise rework, and build greater clinical and regulatory confidence in nano-enabled hydrogel technologies.

While hydrogels have long been known to medical practitioners, and their use widespread, their vast potential has largely lain fallow. Nanotechnology now enables us to use these biocompatible soft materials for a range of highly innovative uses such as tissue scaffolds, cell delivery and targeted drug release. The hydrogel revolution is well underway, and we are about to see its most transformative applications.