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Abstract Background Capacitively coupling electric fields (CCEF) is a method of non-invasive biophysical stimulation that enhances fracture repair and spinal fusion. This multicentre randomized controlled trial aimed to further examine the roles of CCEF in (1) the resolution of vertebral bone marrow oedema (VBME) using a follow-up MRI study and (2) pain relief, analgesic drug consumption and quality of life improvement in stimulated patients who were referred with acute vertebral fragility fractures (VFFs) compared to non-stimulated patients. Methods Between September 2016 and December 2019, patients who were referred to the spine centres that participated in this multicentre randomized clinical study with acute VFFs of type OF1 or OF2 were included in the present study. All the VFFs were conservatively managed according to Good Clinical Practice. Moreover, the patients were randomized into two groups: the CCEF group received, as an adjunct to the clinical study protocol, biophysical stimulation with a CCEF device (Osteospine, IGEA) for 8 h per day for 60 days, whereas the control group was treated according to the clinical study protocol. At baseline (T0), the 30-day follow-up (T1), the 60-day follow-up (T2), and the 6-month follow-up (T3), each patient underwent clinical evaluation using the Visual Analogue Scale (VAS) for Pain and the Oswestry Disability Index (ODI). Analgesic therapy with paracetamol 1000 mg tablets for 7 days—or longer, depending on the pain intensity—was performed; patients were required to report their paracetamol consumption on a specific sheet between study day 8 to 180 days of follow-up. MRI studies of the thoracolumbar spine were performed at 0 (T0), 30 (T1) and 60 days of follow-up (T2) using a 1.5-T MRI system in all of the centres that took part in the study. For each VBME area examined via MRI, the vertebral body geometry (i.e. anterior wall height/posterior wall height and vertebral kyphosis) were assessed. Results A total of 66 patients (male: 9, 13.63%; mean age: 73.15 years old) with 69 VFFs were included in the present study and randomized as follows: 33 patients were included in the control group and the remaining 33 patients were randomized into the CCEF group. In the CCEF group, good compliance with CCEF therapy was observed (adherence = 94%), and no adverse effects were recorded. In the stimulated patients, faster VBME resolution and significantly less vertebral body collapse during follow-up were observed compared to the control patients. Moreover, in the active group, faster pain reduction and improvement in the ODI mean score were observed. Stimulated patients also reported a significantly lower paracetamol consumption rate from the third follow-up after treatment until the 6-month follow-up. In terms of sex-related differences, in the CCEF group, VBME showed a faster resolution in male patients compared with females. Conclusion Biophysical stimulation with CCEF, as an adjunct to traditional conservative treatment, is a useful tool to hasten the VBME resolution process and prevent vertebral body deformation. These MRI findings also correlate with faster back pain resolution and quality of life improvement. From the third follow-up after treatment until the 6-month follow-up, stimulated patients reported a significantly lower paracetamol consumption than control patients, even though back pain and quality of life showed no significant differences between the two groups. Level of evidence II. Trial Registration Register: ClinicalTrials.gov, number: NCT05803681.

Raised life expectancy and aging of the general population are associated with an increased concern for fragility fractures due to factors such as osteoporosis, reduced bone density, and an higher risk of falls. Among these, the most frequent are vertebral compression fractures (VCF), which can be clinically occult. Once the diagnosis is made, generally thorough antero-posterior and lateral views of the affected spine at the radiographs, a comprehensive workup to assess the presence of a metabolic bone disease or secondary causes of osteoporosis and bone frailty is required. Treatment uses a multimodal management consisting of a combination of brace, pain management, bone metabolism evaluation, osteoporosis medication and has recently incorporated biophysical stimulation, a noninvasive technique that uses induced electric stimulation to improve bone recovery through the direct and indirect upregulation of bone morphogenic proteins, stimulating bone formation and remodeling. It contributes to the effectiveness of the therapy, promoting accelerated healing, supporting the reduction of bed rest and pain medications, improving patients’ quality of life, and reducing the risk to undergo surgery in patients affected by VCFs. Therefore, the aim of this review is to outline the fundamental concepts of multimodal treatment for VCF, as well as the present function and significance of biophysical stimulation in the treatment of VCF patients.

Bioelectronic bone implants are being widely recognized as a promising technology for highly personalized bone/implant interface sensing and biophysical therapeutic stimulation. Such bioelectronic devices are based on an innovative concept with the ability to be applied to a wide range of implants, including in fixation and prosthetic systems. Recently, biointerface sensing using capacitive patterns was proposed to overcome the limitations of standard imaging technologies and other non-imaging technologies; moreover, electric stimulation using capacitive patterns was proposed to overcome the limitations of non-instrumented implants. We here provide an innovative low-power miniaturized electronic system with ability to provide both therapeutic stimulation and bone/implant interface monitoring using network-architectured capacitive interdigitated patterns. It comprises five modules: sensing, electric stimulation, processing, communication and power management. This technology was validated using in vitro tests: concerning the sensing system, its ability to detect biointerface changes ranging from tiny to severe bone-implant interface changes in target regions was validated; concerning the stimulation system, its ability to significantly enhance bone cells' full differentiation, including matrix maturation and mineralization, was also confirmed. This work provides an impactful contribution and paves the way for the development of the new generation of orthopaedic biodevices.

Current treatment of chronic musculoskeletal diseases does not give sufficient results despite the implementation of novel drugs and techniques in orthopaedics and physical therapy. For instance, osteoporosis treatment is currently mainly limited to drug application, while the goal of osteoarthritis treatment is to mitigate pain symptoms through physical therapy. The main therapeutic principle in the management of osteoporosis is not only to increase bone mass, but also to improve bone and the cartilage quality, which depends on the biomechanical balance. Therefore, there is a strong demand for advanced technologies that would safely and non-invasively accelerate cartilage regeneration and improve bone density. Ten years ago, a new state-of-the-art technology - “Molecular biophysical stimulation therapy (MBST)”, specifically nuclear magnetic resonance therapy, emerged on the medical technology market and until now, it has shown successful results in the conservative treatment of musculoskeletal disorders, including back pain. The aim of this review is to provide an integrated, synthesized overview of the current evidence of efficacy of MBST for managing chronic musculoskeletal disorders.

Herein we report the synthesis of a ferroelectric composed of chitosan (C)/barium titanate (BT) nanoparticles (NPs) with enhanced biocompatibility, non-toxicity, and piezoelectric behavior that can be advantageously used in biomedical applications. FTIR and SEM measurements were performed to assess the mechanism of interaction between the C matrix and BT NPs and their correlation with the biological responses. The dielectric measurements of the as-prepared composites reveal that incorporation of 50% BT NPs in the chitosan matrix leads to a steady increase of the dielectric constant as compared with neat chitosan films. The ferroelectric behavior of the sample was confirmed by the values of the loss factor (0.21-0.003) in the analyzed frequency range (10 -1 -10 6 Hz). This behavior suggests that ferroelectric C/BT nanocomposites can act as an active material that promotes accelerated bone regeneration.

Phalangeal fractures are common events among the upper limbs accounting for 10% of all human body fractures. Fracture complete healing process may persevere several months or years. Most phalangeal fractures present favorable union within 3 to 6 weeks. In the literature, biophysical stimulation has yielded favorable outcomes in the treatment of hand fractures. A survey involving hospitals in the US reported the use of biophysical stimulation (72%) in relation to nonhealing fractures at three months after trauma. A noninvasive procedure such as biophysical stimulation may be preferential prior to consideration of invasive procedures. In this retrospective study, we analyzed 80 phalangeal fractures, 43 of which did not show any radiographic sign of healing 30 days after surgery; on radiograms, we calculated radiographic data and the total active motion (TAM) for clinical comparison. All radiographic images were evaluated using Adobe Photoshop CS3 (version 10.0, Adobe Systems Inc., San Jose, CA, USA). We calculated the index of relative bone healing each month after surgery starting from 30 days, which was considered as T1, and followed up for a total of 6 months after stimulation (T6) with better results in stimulated groups. We concluded that prompt administration of biophysical stimulation supports fracture healing and yields an important improvement in the union rate compared with nontreatment. Above all, our patients experienced less injury-related distress between the fracture and repair period, which consequently reduced immobilization time, envisaging an early rehabilitation interval, with a better patient hand outcome.

Osteoarthritis (OA) is the most prevalent degenerative joint disease and the main cause of pain and disability in elderly people. OA currently represents a significant social health problem, since it affects 250 million individuals worldwide, mainly adults aged over 65. Although OA is a multifactorial disease, depending on both genetic and environmental factors, it is reported that joint degeneration has a higher prevalence in former athletes. Repetitive impact and loading, joint overuse and recurrent injuries followed by a rapid return to the sport might explain athletes’ predisposition to joint articular degeneration. In recent years, however, big efforts have been made to improve the prevention and management of sports injuries and to speed up the athletes’ return-to-sport. Biophysics is the study of biological processes and systems using physics-based methods or based on physical principles. Clinical biophysics has recently evolved as a medical branch that investigates the relationship between the human body and non-ionizing physical energy. A physical stimulus triggers a biological response by regulating specific intracellular pathways, thus acting as a drug. Preclinical and clinical trials have shown positive effects of biophysical stimulation on articular cartilage, subchondral bone and synovia. This review aims to assess the role of pulsed electromagnetic fields (PEMFs) and extracorporeal shockwave therapy (ESWT) in the prevention and treatment of joint degeneration in athletes.

Biophysical stimulation regulates stem cell functions, including proliferation and differentiation. Matrix nanotopography and external forces, such as electromagnetic fields (EMF), can enhance this stimulation. Here, it is demonstrated that biophysical multiple cues coordinated from electromagnetized Au‐nanoparticles‐decorated polymer nanofiber under EMF significantly regulate the adhesion, alignment, proliferation, and lineage commitment of hMSCs. Without EMF, matrix cues of electrical conductivity and nanodotted fibrous topography accelerate the anchorage and spreading of hMSCs. Of note, EMF synergizes with the matrix cues to enhance cellular behaviors, resulting in elongated and aligned cells along the field direction. Microtubules are highly polymerized, acetylated, and aligned, playing an active role in these events. Actin filaments also develop in parallel with the microtubules, facilitating actin‐microtubule crosstalks. These phenomena lead to changes in the nuclear mechanics of hMSCs, including elongated nuclear shape and decondensed chromatins with histone acetylation. The EMF+matrix‐stimulated hMSCs express genes related to microtubule organization and euchromatin, as revealed by RNA sequencing, and show chromatin accessibility with enrichment of genes related to mechanotransduction and lineage specification, as analyzed by ATAC sequencing. The EMF+matrix biophysical stimulation further increases the capacity for lineage specification (predominantly towards osteogenic, myogenic, and tenogenic), offering a promising bioengineering platform for stem cell engineering and therapies. [ABSTRACT FROM AUTHOR]

Current treatment of chronic musculoskeletal diseases does not give sufficient results despite the implementation of novel drugs and techniques in orthopaedics and physical therapy. For instance, osteoporosis treatment is currently mainly limited to drug application, while the goal of osteoarthritis treatment is to mitigate pain symptoms through physical therapy. The main therapeutic principle in the management of osteoporosis is not only to increase bone mass, but also to improve bone and the cartilage quality, which depends on the biomechanical balance. Therefore, there is a strong demand for advanced technologies that would safely and non-invasively accelerate cartilage regeneration and improve bone density. Ten years ago, a new state-of-the-art technology - "Molecular biophysical stimulation therapy (MBST)", specifically nuclear magnetic resonance therapy, emerged on the medical technology market and until now, it has shown successful results in the conservative treatment of musculoskeletal disorders, including back pain. The aim of this review is to provide an integrated, synthesized overview of the current evidence of efficacy of MBST for managing chronic musculoskeletal disorders.

While several studies investigated the effects of mechanical or electrical stimulation on osseointegration and bone fracture healing, little is known about the molecular and cellular impact of combined biophysical stimulation on peri-implant osseointegration. Therefore, we established an in vitro system, capable of applying shear stress and electric fields simultaneously. Capacitively coupled electric fields were used for electrical stimulation, while roughened Ti6Al4V bodies conducted harmonically oscillating micromotions on collagen scaffolds seeded with human osteoblasts. Different variations of single and combined stimulation were applied for three days, while samples loaded with Ti6Al4V bodies and untreated samples served as control. Metabolic activity, expression of osteogenic markers and bone remodeling markers were investigated. While combined stimulation showed no substantial benefit compared to sole mechanical stimulation, we observed that 25 µm micromotions applied by roughened Ti6Al4V bodies led to a significant increase in gene expression of osteocalcin and tissue inhibitor of metalloprotease 1. Additionally, we found an increase in metabolic activity and expression of bone remodeling markers with reduced procollagen type 1 synthesis after 100 mVRMS electrical stimulation. We were able to trigger specific cellular behaviors using different biophysical stimuli. In future studies, different variations of electrical stimulation will be combined with interfacial micromotions.

ObjectiveChronic nerve compression (CNC) injuries occur when peripheral nerves are subjected to sustained mechanical forces, with increasing evidence implicating Schwann cells as key mediators. Integrins, a family of transmembrane adhesion molecules that are capable of intracellular signaling, have been implicated in a variety of biological processes such as myelination and nerve regeneration. In this study, we seek to define the physical stimuli mediating demyelination and to determine whether integrin plays a role in the demyelinating response.MethodsWe used a previously described in vitro model of CNC injury where myelinating neuron-Schwann cell cocultures were subjected to independent manipulations of hydrostatic pressure, hypoxia, and glucose deprivation in a custom bioreactor. We assessed whether demyelination increased in response to applied manipulation and determined whether integrin-associated signaling cascades are upregulated.ResultsBiophysical stimulation of neural tissue induced demyelination and Schwann cell proliferation without neuronal or glial cytotoxicity or apoptosis. Although glucose deprivation and hypoxia independently had minor effects on myelin stability, together they potentiated the demyelinating effects of hydrostatic compression, and in combination, significantly destabilized myelin. Biophysical stimuli transiently increased phosphorylation of the integrin-associated tyrosine kinase Src within Schwann cells. Silencing this integrin signaling cascade blocked Src activation and prevented pressure-induced demyelination. Colocalization analysis indicated that Src is localized within Schwann cells.InterpretationThese results indicate that myelin is sensitive to CNC injury and support the novel concept that myelinating cocultures respond directly to mechanical loading via activating an integrin signaling cascade.

Ample proof showed that non‐coding RNAs (ncRNAs) play a crucial role in proliferation and differentiation of osteoblasts and bone marrow stromal cells (BMSCs). Varied forms of biophysical stimuli like mechanical strain, fluid shear stress (FSS), microgravity and vibration are verified to regulate ncRNAs expression in osteogenic differentiation and influence the expression of target genes associated with osteogenic differentiation and ultimately regulate bone formation. The consequences of biophysical stimulation on osteogenic differentiation validate the prospect of exercise for the prevention and treatment of osteoporosis. In this review, we tend to summarize the studies on regulation of osteogenic differentiation by ncRNAs beneath biophysical stimulation and facilitate to reveal the regulatory mechanism of biophysical stimulation on ncRNAs, and provide an update for the prevention of bone metabolism diseases by exercise. [ABSTRACT FROM AUTHOR]

Phalangeal fractures are common events among the upper limbs accounting for 10% of all human body fractures. Fracture complete healing process may persevere several months or years. Most phalangeal fractures present favorable union within 3 to 6 weeks. In the literature, biophysical stimulation has yielded favorable outcomes in the treatment of hand fractures. A survey involving hospitals in the US reported the use of biophysical stimulation (72%) in relation to nonhealing fractures at three months after trauma. A noninvasive procedure such as biophysical stimulation may be preferential prior to consideration of invasive procedures. In this retrospective study, we analyzed 80 phalangeal fractures, 43 of which did not show any radiographic sign of healing 30 days after surgery; on radiograms, we calculated radiographic data and the total active motion (TAM) for clinical comparison. All radiographic images were evaluated using Adobe Photoshop CS3 (version 10.0, Adobe Systems Inc., San Jose, CA, USA). We calculated the index of relative bone healing each month after surgery starting from 30 days, which was considered as T1, and followed up for a total of 6 months after stimulation (T6) with better results in stimulated groups. We concluded that prompt administration of biophysical stimulation supports fracture healing and yields an important improvement in the union rate compared with nontreatment. Above all, our patients experienced less injury-related distress between the fracture and repair period, which consequently reduced immobilization time, envisaging an early rehabilitation interval, with a better patient hand outcome.

Osteoarthritis (OA) is the most prevalent degenerative joint disease and the main cause of pain and disability in elderly people. OA currently represents a significant social health problem, since it affects 250 million individuals worldwide, mainly adults aged over 65. Although OA is a multifactorial disease, depending on both genetic and environmental factors, it is reported that joint degeneration has a higher prevalence in former athletes. Repetitive impact and loading, joint overuse and recurrent injuries followed by a rapid return to the sport might explain athletes' predisposition to joint articular degeneration. In recent years, however, big efforts have been made to improve the prevention and management of sports injuries and to speed up the athletes' return-to-sport. Biophysics is the study of biological processes and systems using physics-based methods or based on physical principles. Clinical biophysics has recently evolved as a medical branch that investigates the relationship between the human body and non-ionizing physical energy. A physical stimulus triggers a biological response by regulating specific intracellular pathways, thus acting as a drug. Preclinical and clinical trials have shown positive effects of biophysical stimulation on articular cartilage, subchondral bone and synovia. This review aims to assess the role of pulsed electromagnetic fields (PEMFs) and extracorporeal shockwave therapy (ESWT) in the prevention and treatment of joint degeneration in athletes.

Cellular reprogramming technologies have been developed with different physicochemical factors to improve the reprogramming efficiencies of induced pluripotent stem cells (iPSCs). Ultrasound is a clinically applied noncontact biophysical factor known for regulating various cellular behaviors but remains uninvestigated for cellular reprogramming. Here, we present a new reprogramming strategy using low-intensity ultrasound (LIUS) to improve cellular reprogramming of iPSCs in vitro and in vivo. Under 3D microenvironment conditions, increased LIUS stimulation shows enhanced cellular reprogramming of the iPSCs. The cellular reprogramming process facilitated by LIUS is accompanied by increased mesenchymal to epithelial transition and histone modification. LIUS stimulation transiently modulates the cytoskeletal rearrangement, along with increased membrane fluidity and mobility to increase HA/CD44 interactions. Furthermore, LIUS stimulation with HA hydrogel can be utilized in application of both human cells and in vivo environment, for enhanced reprogrammed cells into iPSCs. Thus, LIUS stimulation with a combinatorial 3D microenvironment system can improve cellular reprogramming in vitro and in vivo environments, which can be applied in various biomedical fields.

Clinical biophysics investigates the relationship between non-ionizing physical energy and the human body. This narrative review aims to summarize the current evidence on the efficacy of PEMF-therapy in the promotion of fracture healing. The effectiveness of PEMFs has been deeply investigated in preclinical in vitro ed in vivo studies and level-I clinical studies. All these studies depicted only PEMF-devices with specific physical wave features - i.e. pulse shape, frequency and amplitude- could significantly promote bone repair. Moreover, the dose-response relationship was also defined in preclinical studies, thus providing the minimum exposure time needed in PEMF-therapy. PEMFs are currently employed in the management several bone injuries, including acute fractures at non-union risk, non-unions, osteotomies, stress fractures and osteonecrosis. Moreover, several ongoing studies are investigating the effectiveness of PEMFs on emerging clinical conditions, thus the indications to PEMF-therapy could potentially raise in future years., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

While several studies investigated the effects of mechanical or electrical stimulation on osseointegration and bone fracture healing, little is known about the molecular and cellular impact of combined biophysical stimulation on peri-implant osseointegration. Therefore, we established an in vitro system, capable of applying shear stress and electric fields simultaneously. Capacitively coupled electric fields were used for electrical stimulation, while roughened Ti6Al4V bodies conducted harmonically oscillating micromotions on collagen scaffolds seeded with human osteoblasts. Different variations of single and combined stimulation were applied for three days, while samples loaded with Ti6Al4V bodies and untreated samples served as control. Metabolic activity, expression of osteogenic markers and bone remodeling markers were investigated. While combined stimulation showed no substantial benefit compared to sole mechanical stimulation, we observed that 25 µm micromotions applied by roughened Ti6Al4V bodies led to a significant increase in gene expression of osteocalcin and tissue inhibitor of metalloprotease 1. Additionally, we found an increase in metabolic activity and expression of bone remodeling markers with reduced procollagen type 1 synthesis after 100 mV RMS electrical stimulation. We were able to trigger specific cellular behaviors using different biophysical stimuli. In future studies, different variations of electrical stimulation will be combined with interfacial micromotions.

Biophysical stimulation to enhance bone fracture repair and bone regenerate maturation to restore its structural strength must rely on both the biological and biomechanical principle according to the local tissue environment and the type of mechanical stress to be born by the skeletal joint system. This paper reviews the possible interactions between biophysical stimuli and cellular responses in healing bone fractures and proceeds to speculate the prospects and limitations of different experimental models in evaluating and optimising such non-invasive interventions. It is important to realize that bone fracture repair has several pathways with various combinations of bone formation mechanisms, but there may only be one bone remodeling principle regulated by the hypothesis proposed by Wolff. There are different mechanical and biophysical stimuli that could provide effective augmentation of fracture healing and bone regenerate maturation. The key requirements of establishing these positive interactions are to define the precise cellular response to the stimulation signal in an in vitro environment and to use well-established animal models to quantify and optimise the therapeutic regimen in a time-dependent manner. This can only be achieved through research collaboration among different disciplines using scientific methodologies. In addition, the specific forms of biophysical stimulation and its dose effect and application timing must be carefully determined and validated. Technological advances in achieving focalized stimulus delivery with adjustable signal type and intensity, in the ability to monitor healing callus mechanical property non-invasively, and in the establishment of a robust knowledgebase to develop effective and reliable treatment protocols are the essential pre-requisites to make biophysical stimulation acceptable in the main arena of health care. Finally, it is important to bear in mind that successful fracture repair or bone regeneration through callus distraction without adequate remodeling process through physiological loading would seriously undermine the value of biophysical stimulation in meeting the biomechanical demand of a long bone.

The article discusses a study which examined the effects of pulsed electromagnetic fields (PEMFs) on patients who underwent bone marrow-derived cells (BMDCs) transplantation for osteochondral lesions of the talus (OLT). Topics covered include the advantages of biophysical stimulation with PEMFs, the superior clinical outcome found in the group with higher American Orthopaedic Foot and Ankle Society (AOFAS) score and the pain control experienced after biophysical stimulation.

Nerve regeneration following traumas remains an unmet challenge. The application of pulsed electromagnetic field (PEMF) stimulation has gained traction for a minimally invasive regeneration of nerves. However, a systematic exploration of different PEMF parameters influencing neuron function at a cellular level is not available. In this study, we exposed neuroblastoma F11 cells to PEMF to trigger beneficial effects on neurite outgrowth. Different carrier frequencies, pulse repetition frequencies, and duty cycles were screened with a custom ad hoc setup to find the most influential parameters values. A carrier frequency of 13.5 MHz, a pulse repetition frequency of 20 Hz, and a duty cycle of 10% allowed maximal neurite outgrowth, with unaltered viability with respect to non-stimulated controls. Furthermore, in a longer-term analysis, such optimal conditions were also able to increase the gene expression of neuronal expression markers NeuN and Tuj-1 and transcription factor Ngn1. Finally, the same optimal stimulation conditions were also applied to THP-1 macrophages, and both pro-inflammatory (TNF-α, IL-1β, IL-6, IL-8) and anti-inflammatory cytokines (IL-10, CD206) were analyzed. The optimal PEMF stimulation parameters did not induce differentiation towards an M1 macrophage phenotype, decreased IL-1β and IL-8 gene expression, decreased TNF-α and IL-8 cytokine release in M1-differentiated cells, increased IL-10 and CD206 gene expression, as well as IL-10 cytokine release in M0 cells. The specific PEMF stimulation regime, which is optimal in vitro, might have a high potential for a future in vivo translation targeting neural regeneration and anti-inflammatory action for treating peripheral nerve injuries.