Advancements and future directions in nerve and salivary gland treatments: a comprehensive review

Surgical Interventions

Peripheral nerve injuries are commonly managed through surgical interventions aimed at repairing or reconstructing damaged nerves. Neurorrhaphy, the direct suturing of severed nerve ends, is often performed when there is minimal nerve gap [7]. In cases where there is a significant gap, nerve grafting is employed, with autografts (using the patient's own nerve tissue) being the gold standard due to their biocompatibility and ability to support axonal growth [8]. However, autografting is limited by donor site morbidity and the availability of suitable donor nerves. Allografts and synthetic nerve conduits are alternative options, but they come with challenges such as immune rejection and inferior functional outcomes compared to autografts [9].

Regenerative Medicine Approaches

Advancements in regenerative medicine have introduced innovative strategies for nerve regeneration. Stem cell therapy, particularly the use of mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs), has shown promise in promoting nerve repair and functional recovery [4]. These cells can differentiate into various cell types, secrete neurotrophic factors, and modulate the immune response to facilitate regeneration [10].

Biomaterials and scaffolds play a crucial role in nerve regeneration by providing structural support and guiding axonal growth. Biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA) and natural materials like collagen and chitosan have been extensively studied [11]. Electrospun nanofibers, for example, mimic the extracellular matrix and enhance cell adhesion and proliferation [12]. Additionally, hydrogels are being explored for their ability to deliver cells and growth factors directly to injury sites, providing a conducive environment for nerve regeneration [13].

Pharmacological interventions complement surgical and regenerative strategies by addressing the molecular pathways involved in nerve injury and repair. Neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor (BDNF), are administered to support neuronal survival and axonal growth [14]. Anti-inflammatory drugs and antioxidants are also used to mitigate secondary damage caused by inflammation and oxidative stress, thereby enhancing the regenerative process [15].

Conventional Therapies

Salivary gland dysfunction, often resulting from Sjögren's syndrome, radiation therapy, or trauma, leads to xerostomia and associated complications like dental caries and oral infections. Conventional treatments focus on symptom management, including saliva substitutes, sialogogues (agents that stimulate saliva production), and meticulous oral hygiene practices [16]. While these approaches provide temporary relief, they do not address the underlying glandular dysfunction, necessitating the exploration of regenerative therapies.

Regenerative Medicine and Tissue Engineering

Regenerative medicine offers potential solutions for restoring salivary gland function. Stem cell therapy, particularly the use of salivary gland stem cells and MSCs, aims to regenerate damaged glandular tissue [17]. These stem cells can differentiate into acinar and ductal cells, which are essential for saliva production and secretion [18]. Tissue engineering approaches involve creating bioengineered salivary glands using scaffolds seeded with stem cells and growth factors to promote organogenesis [19].

Biomaterials used in salivary gland tissue engineering must support cell adhesion, proliferation, and differentiation. Natural polymers like gelatin and hyaluronic acid, as well as synthetic polymers such as PLGA, are commonly employed [20]. Three-dimensional (3D) bioprinting technology is emerging as a method to fabricate complex glandular structures with precise architectural features, allowing for the recreation of the intricate cellular organization of salivary glands [21]. Additionally, bioreactors are being developed to provide the necessary mechanical and biochemical stimuli to enhance tissue maturation and functionality [22].

Pharmacological and gene therapy approaches aimed at promoting salivary gland regeneration include the use of growth factors, such as epidermal growth factor and BDNF, and agents that enhance cellular proliferation and differentiation [11]. Gene therapy is being explored to deliver genes encoding for neurotrophic factors and other proteins essential for glandular regeneration [23]. Viral and non-viral vectors are utilized to achieve targeted gene delivery and sustained expression of therapeutic genes, thereby enhancing the regenerative capacity of salivary gland tissues [24].

Nerve Regeneration

A notable clinical case involved a patient with a complete transection of the median nerve treated with a combination of autografting and MSC therapy. Postoperative follow-up over 12 months demonstrated significant functional recovery, including improved motor control and sensory perception [25]. This case highlights the potential synergistic effects of combining surgical and regenerative approaches for enhanced nerve regeneration. Another study reported on the use of iPSC-derived neural progenitor cells in patients with spinal cord injuries, resulting in partial restoration of motor function and reduced neuropathic pain [26]. These clinical examples underscore the promising outcomes of integrating stem cell therapies with conventional surgical techniques.

Salivary Gland Restoration

In a clinical trial, patients with radiation-induced xerostomia received injections of bioengineered salivary gland organoids derived from iPSCs. The treatment led to partial restoration of salivary flow and alleviation of xerostomia symptoms over a six-month period [27]. This case underscores the feasibility of using advanced tissue engineering techniques to restore salivary gland function in patients with severe glandular damage. Additionally, a study involving the transplantation of MSCs into patients with Sjögren's syndrome-related salivary gland dysfunction reported improved glandular function and reduced symptoms of dry mouth [28]. These clinical outcomes demonstrate the potential of regenerative therapies to provide long-term solutions for salivary gland dysfunction.

Nerve Regeneration

Despite significant advancements, nerve regeneration therapies face several challenges. Autografting is limited by donor site availability and associated morbidity, making it less feasible for extensive nerve injuries [29]. Stem cell therapies, while promising, are hindered by issues related to cell survival, integration, and potential tumorigenicity. Ensuring that transplanted stem cells differentiate appropriately and integrate seamlessly with host tissues remains a critical hurdle [8]. Biomaterial scaffolds, although effective in guiding axonal growth, require precise design to match the mechanical and biochemical properties of native nerve tissue. Achieving the optimal balance between scaffold degradation rate and tissue regeneration speed is essential for successful outcomes [9].

Salivary Gland Restoration

Salivary gland tissue engineering is still in its early stages, with challenges related to replicating the complex cellular architecture and functional aspects of the glands. The intricate network of acinar and ductal cells, along with the necessary vascularization and innervation, poses significant obstacles for bioengineered glandular tissues [30]. Ensuring the long-term functionality and integration of bioengineered glands with existing oral structures is another major challenge [31]. Additionally, the high cost and complexity of tissue engineering techniques limit their widespread clinical application, necessitating the development of more cost-effective and scalable solutions [21].

Personalized Medicine and Precision Therapies

The future of nerve and salivary gland treatments lies in personalized medicine, where therapies are tailored to individual genetic and molecular profiles. Advances in genomics and proteomics will enable the development of precision therapies that target specific pathways involved in nerve and glandular dysfunction [32]. Personalized approaches will enhance the efficacy of treatments by addressing the unique biological characteristics of each patient, thereby improving outcomes and reducing adverse effects.

Gene Editing and Clustered Regularly Interspaced Short Palindromic Repeats Technology

Gene editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9, hold promise for correcting genetic defects that contribute to nerve and salivary gland diseases. These technologies can be used to enhance the regenerative capacity of cells or to introduce genes that promote tissue repair and functional recovery [15]. By precisely modifying the genetic makeup of stem cells or glandular cells, CRISPR technology can facilitate the development of more effective and targeted regenerative therapies [17].

Nanotechnology and Drug Delivery Systems

Nanotechnology offers innovative solutions for targeted drug delivery and controlled release of therapeutic agents. Nanoparticles can be engineered to deliver neurotrophic factors, anti-inflammatory drugs, and other bioactive molecules directly to injury sites, enhancing the efficacy and reducing systemic side effects [33]. Additionally, nanostructured biomaterials can provide a conducive environment for cell growth and differentiation, further improving regenerative outcomes [34]. The integration of nanotechnology with regenerative medicine approaches is expected to revolutionize the treatment of nerve and salivary gland dysfunctions [21].

Integration of Artificial Intelligence (AI)

Artificial intelligence (AI) and machine learning algorithms can revolutionize the diagnosis, treatment planning, and monitoring of nerve and salivary gland conditions. AI can analyze complex datasets to identify patterns and predict treatment outcomes, enabling more informed clinical decision-making [24]. In regenerative medicine, AI can optimize the design of biomaterials, predict cell differentiation pathways, and personalize treatment protocols based on patient-specific data [33]. The integration of AI with regenerative therapies has the potential to enhance the precision and effectiveness of treatments, leading to better patient outcomes [24].

Advances in Biomaterials and Scaffold Design

Future biomaterials will be designed with enhanced bioactivity, biodegradability, and mechanical properties to better mimic native tissues. Smart biomaterials that respond to environmental cues and release therapeutic agents in a controlled manner are expected to improve tissue regeneration outcomes [21]. Advances in scaffold design, including the use of 3D bioprinting and biofabrication techniques, will allow for the creation of more complex and functional tissue structures [20]. These innovations will facilitate the regeneration of intricate nerve and glandular tissues, overcoming current limitations and expanding the potential applications of regenerative medicine [35].