Research Initiatives
Our research in different fields aims to provide innovative solutions to enhance the procedures and quality of life of each and every patient in our care. Our main interest has always been to concentrate on research that can progress from the laboratory to the patient's bedside with minimal delay. We are involved in a whole range of clinical - and laboratory research. Our main laboratory projects are discussed below.
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For our complete range of research projects and prospective GRANTS for research positions, click on the link to return to the Home page.
Facial Palsy - Reconstructive Surgery
Free Functional MuscleTransfer ( FFMT)
Project 1 - Optimizing Nerve Regeneration
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Facial palsy affects around 23 per 100 000 people per year and between 0.8 and 2.1 children are born with facial paralysis. The effects of facial nerve paralysis are profound for all patients: asymmetry of the face, difficulty in eating or speaking, problems with eye closure and difficulty expressing their feelings are only some of the few problems these patients have to live with. Reconstructive surgery has improved the treatment of permanent facial paralysis greatly since the mid-eighties, however, surgery still cannot produce a guaranteed spontaneous smile in response to emotion in all cases. Surgery normally involves a complex series of at least two surgeries and one of the major problems is a lack of suitable alternative nerves to use in the human body. Our current research is directed towards minimizing donor site morbidity by perfecting the technique to use an artificial nerve instead of a donor nerve from the patient with the subsequent morbidity. In addition, scientists do not yet understand all the mechanisms by which a nerve heals and what we can do to improve the regenerative process. The second part of our research is aimed at investigating this regeneration process to establish whether we can find the silver bullet to optimize the regeneration process in all cases and improve the percentage of optimal results in patients. We are also making a contribution to an international panel to optimize the treatment and post-operative facial therapy in children with facial paralysis.
(Prof. Dr. med. Adriaan Grobbelaar & PD.Dr. med.Ioana Lese - Plastic Surgery)
Graphic images of two different stages in the facial re-animation surgical process
The first stage of the operation - Facial re-animation
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A new nerve graft is laid on from the functional to the non-functional part of the face in preparation for the introduction of the new muscle (FFMT) during the second phase of the operation displayed in the image below.
The second stage of the operation
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The transfer of the free functional muscle to replace the non-functional muscle on the paralyzed side of the face.
Project 2​ - Patient Education
For many patients affected by facial palsy, reconstructive surgery represents the only viable chance to regain functional control over their facial expressions. In addition to the physical symptoms such as problems with eye closure, oral incompetence, difficulties in articulation, and lack the ability to smile, facial palsy also has severe psychological and social impacts.
Therefore, many people suffering from this condition seek such surgical solutions. In cases of complete facial paralysis, the treatment of choice is free functional muscle transfer (FFMT), which means transplanting new muscles into the face and re-establishing a functional nerve input. These are highly complex microsurgical procedures often involving two or more operations. Due to this complexity, patients’ ability to fully understand and retain all the information provided during a traditional consultation varies significantly and poses a barrier to truly informed consent, especially in children.
Furthermore, the surgeons can only put the muscles and nerves in place, yet it is up to the patient to learn how to use them and retrain a spontaneous smile. The success of these procedures heavily depends on the collaboration and motivation of the patient to engage with the physiotherapist during the lengthy post-operative treatment phase.
As part of our research, we are producing multilingual, animated patient videos and developing an integrated messaging platform that aims to improve patients’ understanding of FFMT surgery, its potential complications, and the recovery period.
Our aim is that this will not only enhance patients’ satisfaction and engagement during their reconstructive journey but eventually also improve the final result of the procedure.
(Prof. Dr. med. Adriaan Grobbeaar & Dr. med. Cédric Zubler - Plastic Surgery)
Short video clip explaining free functional muscle transfer (FFMT) to patients and parents.
The complete procedure will be explained by the surgeon/s during formal consultation and additional videos will also be provided The videos are available in a number of languages. (Created with the assistance and expertise of Mr. Dimitris Reissis and My Surgery)
Nanotechnology
This image depicts an example of an electro-microscopic image of a nano-particle.
Nanotechnology offers exciting new therapeutic approaches. The small size of the nanoparticles offers great advantages in the field of medicine. They can be specifically designed to include various substances on their surface and also to bind to specific cells. The increase in contact area when using nanoparticles can be helpful in the field of Reconstructive- and Plastic Surgery by delivering specific minerals, such as strontium and zinc, in order to stimulate vascularization, tissue adhesion and promote better wound healing
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Inorganic nanoparticles for seroma management
Seroma formation is a common, yet poorly understood post-operative complication caused by the accumulation of serous fluid following the dissection of extensive skin flaps.
Seromas most commonly occur following abdominoplasty (removal of excess skin and fat from the middle and lower abdomen, mostly for cosmetic purposes), mastectomy (removal of breast tissue) with or without the removal of the axillary lymph nodes, and at the donor site after harvesting the latissimus dorsi muscle for reconstructive purposes.
This serious post-operative complication occurs in almost 79% of patients cases. Due to the high frequency of cases, surgeons have started considering it a side effect, rather than a complication. Therapeutic management is stressful and time-consuming for patients and physicians alike. It includes prolonged hospital stays as a result of the required drainage, associated wound healing problems, repeated admissions to the hospital, and additional corrective surgeries.
Nanotechnology offers numerous new opportunities for clinics. The small dimensions of the nanoparticles, as well as their controllable surface characteristics, can be harnessed for medical purposes. It has been recorded that this treatment has achieved tissue adhesion and strong closure of deep wounds in the skin and liver. More recently, the concept of nano-bridging has been extended from inert nano-particles to nano-materials, exhibiting potent bioactivity, including bioglass/cerium oxide-based hybrid nanoparticles.
In one of our recent studies, it was recorded that the inherent procoagulant, neo-angiogenic, and anti-inflammatory properties of zinc-doped strontium-substituted bioglass/ceria nanoparticles lead to increased skin flap survival. Therefore, the prospect of extending nano-bridging to bioactive nano-particles with procoagulant and tissue regenerative properties for the prevention of seroma is promising. The zinc-doped strontium-substituted bioglass/ ceria nano-particles unify the angiogenic and soft tissue regeneration properties of bioglass with endothelial cell proliferation and vascular sprouting induction, as well as antioxidant properties of ceria. Although both zinc and strontium have angiogenic properties, zinc additionally exhibits anti-inflammatory activity.
Our primary aim is to refine our research, based on these observations to find an innovative solution or solutions for the treatment of seroma.
(PD. Dr. med. Ioana Lese - Consultant - Plastic Surgery)
Hand Surgery
Peripheral Nerve Research
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Traumatic injuries to the nerves of the arm and hand are common and caused by factors ranging from acts of violence, motor vehicle accidents, and recreational activities, to iatrogenic injuries during surgery. The majority of nerve injuries occur in the upper extremity. It is estimated that 1–3% of all upper extremity trauma patients are diagnosed with nerve injuries. These injuries are often severely debilitating, resulting in lifestyle disruptions from loss of function, both at work and in leisure. Moreover, traumatic nerve injuries frequently affect relatively young individuals, resulting in lifelong reductions in quality of life and income.
Despite advances in surgery and neuroscience, the improvement of patient outcomes by the surgical reconstruction of nerve injuries continues to pose challenges. The most severe nerve injuries, in which trauma to the nerve generates a defect between the nerve ends, remain an area in significant need of improvement and further research.
For the repair of mixed or motor nerves, such as the median and ulnar nerves of the hand and arm, studies have demonstrated that bridging the defect with an autograft (your own nerve) results in meaningful recovery in 60–80% of radial and median nerves and 57–60% of ulnar nerves.
Furthermore, there is a general consensus that any regenerative success declines as autografts go beyond 60 mm.
How can we improve nerve regeneration through defects? The research includes bioengineered nerve graft alternatives such as scaffolding and topology, local drug delivery, and supplementing cells. Axonal guidance and non-neuronal cell signaling, including that occurring through the immune system, all contribute to regeneration leading to functional recovery. The longer the nerve defect the more difficult the nerve regeneration. While the cause of limited axon regeneration across long nerve graft alternatives is still controversial, recent results demonstrated the environment of long nerve graft alternatives generates a barrier to axon growth.
Research in our lab focuses on the improvement of nerve regeneration in long nerve auto- and allografts, the nerve-muscle border, and within the muscle (motor mixed nerves) or within the skin (sensory nerves).
(Prof. Dr. med. Esther Vögelin - Chief Physician & Co-Director of Hand Surgery)
Vascularized Decellularized Nerve Grafts in Peripheral Nerve Injuries
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Peripheral nerve injuries are devastating, life-altering injuries. Autologous nerve grafts are the current elective therapy for the repair of these injuries. However, the clinical application of autologous nerve grafts is restricted by limited tissue supply and significant donor site morbidity. Tissue engineering provides new techniques for the repair of peripheral nerve injuries. Decellularized scaffolds, which act as guide conduits for the regenerating nerves, represent a promising approach to increasing the availability of nerve grafts. In this approach, nerve allografts are decellularized to eliminate cells and maintain an extracellular matrix that provides three-dimensional support for the self-repair process and axonal growth without generating an immune response.
So far, only allogeneic nerve conduits have been investigated. We hypothesized that the development of a nerve scaffold with vascular support (i.e., vascularized nerve graft, VNG) may help the regeneration process in vivo, increasing cell engraftment and functional recovery as compared to nonvascularized nerve conduits (NVNC). Therefore, in this project, we will create VNG using perfusion decellularization to facilitate cell removal while preserving the structure and regenerative potential of the extracellular matrix. Decellularized nerve scaffolds will be thoroughly characterized and their vascular bed will be recelluarized in vitro using primary culture of endothelial cells. Finally, the functional recovery of peripheral nerve injuries after nerve repair using either VNG or NVNC will be assessed in vivo.
(Dr. med. Damian Sutter, Consultant - Hand Surgery)
Differences Between Cranial and Peripheral Nerve Regeneration
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Neurons in the peripheral nervous system (PNS) and central nervous system (CNS) differ significantly in their ability to regenerate. While CNS neurons face inhibitory factors and have limited regenerative potential, PNS nerves readily regenerate after injury. The injured neuron activates regeneration-associated genes, facilitating axon regrowth and reconnection with target tissues. The PNS environment, with pro-conductive Schwann cells and absence of inhibitory factors found in CNS white matter, is more conducive to axon regeneration. Motoneurons of peripheral nerves are located in the spinal cord's anterior horn, while cranial motor nerves reside more centrally in the brainstem. In view of the mentioned differences between PNS and CNS the question arises: where do cranial nerves fall? It is the current belief that the regenerative process of cranial nerves follows the peripheral nerve models with exception of the olfactory and optic nerves. Study outcomes on axonal regeneration of brainstem and spinal motoneurons are therefore often broadly applied to all motoneurons in the PNS. However, evidence of previous studies suggests that brainstem motoneurons exhibit distinct protein expression and varying degrees of retrograde cell death in response to nerve transection compared to spinal motoneurons. These data suggest that there exists a difference in the intrinsic response to axon injury between cranial and peripheral nerves, possibly resulting in a different regeneration capacity. To date, a direct qualitative and quantitative comparison of neuromuscular regeneration of brainstem and spinal motoneurons has not been studied.
For the reconstruction of nerve defects, decellularized allograft reconstructions are frequently used in peripheral nerves whereas autograft interposition alongside nerve transfer surgery has represented the state of the art for facial nerve reconstruction so far. In decellularized allografts, the internal structure is preserved, while cellular components including Schwann cells are removed to create a nonimmunogenic graft. However, for large segmental motor nerve injuries, results remain inferior to autograft reconstruction. As of present, descriptions of allograft reconstructions for the facial nerve are limited to isolated cases, with no comprehensive investigation into their neuromuscular regeneration capacity.
This research project aims to investigate and compare the regenerative potential of injured brainstem motoneurons with spinal motoneurons after nerve transection and repair. Specifically, we will test the hypothesis that injured brainstem motoneurons of the facial nerve have a diminished regenerative potential compared to spinal motoneurons of the sciatic nerve. Additionally, we will investigate the difference in neuromuscular regeneration between decellularized allograft and autologous nerve graft reconstruction of the facial nerve. Functional and electrophysiological in vivo examinations of the target muscles will be conducted to measure the quality of reinnervation. Immunohistochemical and electron microscopic assessments on nerve and muscle samples will be obtained to objectify the quantity of axonal regeneration and muscle reinnervation, respectively.
Significant differences could lead to brainstem and spinal motoneurons being treated as two separate entities in future research. The findings of this study may prove essential in comprehending the complex cellular and molecular mechanisms involved in axon regeneration, a prerequisite for developing new strategies in the treatment of peripheral nerve injuries. Furthermore, this study will provide fundamental scientific insights into the neuromuscular regeneration of decellularized allograft reconstruction of the facial nerve.
(Dr. med. Rémy Liechti, Consultant – Hand and Peripheral Nerve Surgery & Dr. med. Njima Schläpfer - Resident – Otolaryngology)
Schematic of the anatomical location of brainstem and spinal motoneurons their axon and motor unit.
The Role of the p75 Neurotrophin Receptor and its Selective Inhibition to Promote Axonal Regeneration of Brainstem and Spinal Motor Neurons
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Peripheral nerve injuries often affect young, working adults. These injuries occur in about 2.6% of upper limb and 1.2% of lower limb trauma cases. Regarding cranial nerves, the facial nerve is the most commonly affected due to head injuries, ear diseases, or surgeries with 13 to 30 out of every 100,000 adults suffering this type of nerve injury every year.
Both peripheral and cranial nerves are classified under the peripheral nervous system (PNS). Most nerves in the PNS are mixed, consisting of nerve fibers (axons) responsible for muscle control and axons for sensation (e.g., touch, pain, and proprioception).
Although nerves in the peripheral nervous system have the ability to regenerate after injury, recovery is often incomplete, leading to lasting functional problems that impact daily life. Key challenges in nerve regeneration include the need for axons to sprout from the injury site, their slow growth rate of approximately 1 mm per day, and the significant loss of neurons due to an intrinsic cell death response following axonal injury. Motor neurons (MNs), which control muscle function, face additional time constraints, as denervated muscles begin to degenerate. Without successful reinnervation within 12 to 18 months, muscle wasting occurs, leading to permanent loss of function.
Each axon is an extension of a cell body, which, in the case of motor neurons (MNs, nerve cells that control muscle function), is located in the central nervous system (CNS). Peripheral nerves that innervate skeletal muscles have their cell bodies in the anterior horn of the spinal cord (spinal motor neurons or spinal MNs), while the cell bodies of cranial nerves are located in the brainstem (brainstem motor neurons or brainstem MNs).
It is the current belief that the regenerative process of cranial nerves follows the peripheral nerve models with exception of the olfactory (smell) and optic (vision) nerves. Therefore, research on nerve regeneration is often broadly applied to all MNs of the PNS in the body. However, there are studies that suggest that brainstem MNs respond differently to injury than spinal MNs. Brainstem motor neurons are considered particularly vulnerable to cell death following axon injury, with loss rates reaching up to 50%.
A protein called the p75 neurotrophin receptor (p75NTR) becomes highly active after nerve injury and plays a key role in determining whether a neuron dies. However, its effects on a neuron with an axonal injury depend on the presence of other receptors and nerve growth factors (neurotrophins). For example, Brain-Derived Neurotrophic Factor (BDNF) binds to the Tropomyosin Receptor Kinase B (TrkB), promoting survival and regeneration, while the intracellular domain (ICD) of p75NTR amplifies this effect by tenfold. On the other hand, the precursor form of the same neurotrophin (pro-BDNF) promotes the initiation of cell death when interacting with p75NTR and another receptor called Sortilin (Figure 1A).
A drug called LM11A-31 is gaining significant attention in brain injury and Alzheimer's disease research because it selectively blocks the p75NTR receptor’s role in triggering cell death. Recent research suggests it might also help peripheral MNs recover by improving muscle reinnervation when applied directly to injured nerves. However, a reliable method for locally delivering the drug over the full period of nerve healing has yet to be developed.
Our research aims to understand how p75NTR influences nerve regeneration in brainstem and spinal MNs after nerve injury and repair. To measure this, we analyze muscle function, electrical nerve activity, axon regrowth, myelination and neuron survival. Furthermore, to investigate the proportion of p75NTR-expressing MNs that promote cell death or survival, we perform immunofluorescence staining of MN cell bodies in the brainstem and spinal cord. This includes co-labeling with p75NTR and Cleaved Caspase-3 (a marker of cell death initiation), allowing us to identify p75NTR-expressing MNs that trigger cell death (Figure 1B). These findings will lay the foundation for our planned next step to test whether blocking p75NTR with LM11A-31 can reduce MN loss and improve recovery. We are collaborating with the Pharmaceutical Technology Research Group at the Department of Chemistry, Biochemistry, and Pharmaceutical Sciences at the University of Bern. They are in the process of developing a biodegradable gel containing LM11A-31, which can be applied around the injured nerve during surgery to ensure continuous local release of the drug throughout the healing process.
By comparing how brainstem and spinal MNs respond to injury and testing LM11A-31 as a targeted treatment, we aim to improve outcomes for patients undergoing nerve repair. Our findings could pave the way for new strategies to prevent neuron loss and accelerate functional recovery, providing hope for improved rehabilitation and a better quality of life for affected patients.
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Schematic of p75NTR signaling pathways in a motor neuron of a peripheral nerve.
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Figure 1: A) p75NTR signaling pathways in a motor neuron of a peripheral nerve. Pro- BDNF binding to the p75NTR and Sortilin induces cell death whereas interaction of the p75NTR ICD with the TrkB receptor improves its affinity for BDNF 10-fold amplifying pro-survival and -regeneration signaling. LM11A-31 selectively inhibits pro-BDNF binding to the p75NTR receptor and Sortilin, thereby reducing cell death signaling. B) Immunofluorescence co-labeling of FG, p75NTR and Cleaved Caspase-3 in the sciatic motor nucleus pool of a spinal cord 1 week after sciatic nerve injury. FG retrograde labeling was performed to ensure exclusive labeling of sciatic MNs. p75NTR-immunoreactive cells are co-expressing Cleaved Caspase-3 initiating apoptosis (arrowheads) while others do not (arrows).
Abbreviations: BDNF brain-derived neurotrophic factor, FG Fluoro-Gold, TrkB tropomyosin kinase receptor B, ICD intracellular domain, ERK extracellular signal regulated kinase, Elk-1 Ets-like kinase 1, MAPK mitogen-activated protein kinase, JNK c-Jun Nterminal.Created with BioRender.com
(Dr. med. Rémy Liechti, Consultant – Hand and Peripheral Nerve Surgery & Dr. med. Njima Schläpfer - Resident – Otolaryngology)
