Indirect Healing Research Articles

Open Reduction and Internal Fixation versus Minimally Invasive Plate Osteosynthesis in Management of Distal Tibia Extra-Articular Fracture (Mini Thesis)

Abstract Background Extra-articular distal tibia fracture is one of the difficult fractures to treat and the optimal treatment remains controversial, however plates seem to be the obvious choice for treating this type of fractures. The mechanism on how to achieve the balance between anatomic reduction and indirect reduction as well as direct and indirect healing remains unclear. Thus, the key point is whether to use ORIF or MIPO in treating fractures. Aim of the Work to provide a complete overview of the optimal plating technique for distal tibia fractures by evaluating and comparing the clinical and functional outcomes of minimally invasive plate osteosynthesis (MIPO) vs Open reduction and internal fixation (ORIF) for treating extra- articular distal tibial fractures. Outcomes of interest include operation time, time to union, non-union, mal-union, infection, secondary operations, and functional outcomes (AOFAS score). Patients and Methods From August 2020 to August 2021, a prospective randomized study was conducted at the department of orthopedic surgery of Ain-shams University Hospital including 36 patients to compare MIPO vs. ORIF in fixation of extra-articular distal tibial fractures. The patients were allotted to the MIPO or ORIF group with the flip of a coin. Results Regarding complications rate, no cases developed infection in MIPO technique. On the other hand, the ORIF technique had an infection incidence of 16.6% overall, with two cases (11.11 %) developing superficial infection and one case (5.56 %) developing deep infection. There was no significant difference in the incidence of mal-union between both techniques with no cases of non-union in both groups. The MIPO group had only one case of sagittal plane malunion (5.56%), compared with no cases in the ORIF group. There was no significant difference between both groups in secondary operations rate, with one case in each group. Conclusion Both MIPO and ORIF have similar therapeutic efficacy regarding the functional outcome and can be used safely in distal tibial extra-articular fractures. Although MIPO is advantageous over ORIF with earlier weight-bearing, earlier union, and clinical lower incidence of infection, it has delayed operation time.

Development of Organoid-Based Cytotherapeutics for Taste Loss Induced By Anti-Cancer Chemotherapy and Radiotherapy

Introduction Ulcerative mucositis and taste loss are common side effects induced by cancer therapy, including chemotherapy and radiation therapy. These conditions cause significant oral pain and loss of taste, impacting food intake and physical health abnormalities such as malnutrition, as well as depression and mental health deterioration, which can affect prognosis. To address these challenges, an appropriate treatment for oral mucositis is required. While various types of oral mucositis treatments have been developed (e.g., patch, spray, ointment), most show indirect healing effects such as pain control and inflammation relief. Thus, a direct method for treating oral lesions should be developed. This research was supported by the Korean Fund for Regenerative Medi- cine (KFRM) grant funded by the Korea Government (the Ministry of Science and ICT, the Ministry of Health & Welfare) (21C0712L1-11). Methods To compensate for the difficulty in supplying human tissue, we conducted preliminary experiments using mice to establish protocols for manufacturing human oral tissue-derived cell therapeutics. we devised an organoid-derived cell sheet transplantation. First, we generated organoids derived from oral mucosa and prepared a cell sheet using a temperature-responsive cell culture dish. The harvested cell sheet was transplanted to the lesion site to enable structural and functional recovery of the oral mucosa and gustatory organs. Results We have developed a cell-therapeutic platform based on regenerative medicine technology to recover oral lesions in cancer chemotherapy and radiotherapy patients. Specifically, we developed a method for producing autologous cell therapeutics. The oral mucosa tissue of a patient scheduled for anticancer treatment was collected, and epithelial cells were obtained from the tissue. Using these cells, we generated organoids with differentiated taste bud cells, and isolated cells from the organoids were seeded onto temperature-responsive cell culture dishes and cultured beyond confluence for the formation of a sheet. We performed immunostaining to detect various types of taste cells in the cell sheet. We also confirmed the success of cell sheet transplantation and the subsequent healing effect. Conclusion Improving the prognosis and acquiring the will to recover of cancer chemotherapy and radiotherapy patients through repairing taste function and rapid healing of lesions are crucial. We have developed a cell therapy technology that enables the structural and functional recovery of the oral mucosa and gustatory organs, providing a promising solution to treat the side effects of anti-cancer treatment. Our research provides an R&D initiative for the treatment and prevention of intractable diseases by culturing, manufacturing, and transplanting living autologous cells.

Effect of uncertain clinical conditions on the early healing and stability of distal radius fractures

Background and objectivesThe healing outcomes of distal radius fracture (DRF) treated with the volar locking plate (VLP) depend on surgical strategies and postoperative rehabilitation. However, the accurate prediction of healing outcomes is challenging due to a range of certainties related to the clinical conditions of DRF patients, including fracture geometry, fixation configuration, and physiological loading. The purpose of this study is to investigate the influence of uncertainty and variability in fracture/fixation parameters on the mechano-biology and biomechanical stability of DRF, using a probabilistic numerical approach based on the results from a series of experimental tests performed in this study. MethodsSix composite radius sawboneses fitted with titanium VLP (VLP 2.0, Austofix) were loaded to failure at a rate of 2 N/s. The testing results of the elastic and plastic behaviour of the VLP were used as inputs for a probabilistic-based computational model of DRF, which simulated mechano-regulated tissue differentiation and fixation elastic capacity at the fracture site. Finally, the probability of success in early indirect healing and fracture stabilisation was predicted. ResultsThe titanium VLP is a strong and ductile fixation whose flexibility and elastic capacity are governed by flexion working length and bone-to-plate distance, respectively. A fixation with optimised designs and configurations is critical to mechanically stabilising the early fracture site. Importantly, the uncertainty and variability in fracture/fixation parameters could compromise early DRF healing. The physiological loading uncertainty is the most adverse factor, followed by the negative impact of uncertainty in fracture geometry. ConclusionsThe VRP 2.0 fixation made of grade II titanium is a desirable fixation that is strong enough to resist irreparable deformation during early recovery and is also ductile to deform plastically without implant failure at late rehabilitation.

A novel biomimetic trabecular bone metal plate for bone repair and osseointegration.

Fracture is one of the most common traumatic diseases in clinical practice, and metal plates have always been the first choice for fracture treatment because of their high strength. However, the bone plates have high elastic modulus and do not match the biomechanics of human bone, which adversely affects callus formation and fracture healing. Moreover, the complex microenvironment in the human body can induce corrosion of metallic materials and release toxic ions, which reduces the biocompatibility of the bone plate, and may necessitate surgical removal of the implant. In this study, tantalum (Ta) was deposited on porous silicon carbide (SiC) scaffolds by chemical vapor deposition technology to prepare a novel porous tantalum (pTa) trabecular bone metal plate. The function of the novel bone plate was evaluated by implantation in an animal fracture model. The results showed that the novel bone plate was effective in fracture fixation, without breakage. Both X-ray and microcomputed tomography analysis showed indirect healing by both pTa trabecular bone metal plates and titanium (Ti) plates; however, elastic fixation and obvious callus formation were observed after fixation with pTa trabecular bone metal plates, indicating better bone repair. Histology showed that pTa promoted the formation of new bone and integrated well with the host bone. Therefore, this novel pTa trabecular bone metal plate has good prospects for application in treating fractures.

Balance Between Mechanical Stability and Mechano-Biology of Fracture Healing Under Volar Locking Plate.

The application of volar locking plate (VLP) is promising in the treatment of dorsally comminuted and displaced fracture. However, the optimal balance between the mechanical stability of VLP and the mechanobiology at the fracture site is still unclear. The purpose of this study is to develop numerical models in conjunction with experimental studies to identify the favourable mechanical microenvironment for indirect healing, by optimizing VLP configuration and post-operative loadings for different fracture geometries. The simulation results show that the mechanical behaviour of VLP is mainly governed by the axial compression. In addition, the model shows that, under relatively large gap size (i.e., 3-5mm), the increase of FWL could enhance chondrocyte differentiation while a large BPD could compromise the mechanical stability of VLP. Importantly, bending moment produced by wrist flexion/extension and torsion moment produced from forearm rotation could potentially hinder endochondral ossification at early stage of healing. The developed model could potentially assist orthopaedic surgeons in surgical pre-planning and designing post-operation physical therapy for treatment of distal radius fractures.

The investigation of bone fracture healing under intramembranous and endochondral ossification

After trauma, fractured bone starts healing directly through bone union or indirectly through callus formation process. Intramembranous and endochondral ossification are two commonly known mechanisms of indirect healing. The present study investigated the bone fracture healing under intramembranous and endochondral ossification by developing theoretical models in conjunction with performing a series of animal experiments. Using experimentally determined mean bone densities in sheep tibia stabilized by the Locking Compression Plate (LCP) fixation system, the research outcomes showed that intramembranous and endochondral ossification can be described by Hill Function with two unique sets of function parameters in mechanical stimuli mediated fracture healing. Two different thresholds exist within the range of mechanical simulation index which could trigger significant intramembranous and endochondral ossification, with a relatively higher bone formation rate of endochondral ossification than that of intramembranous ossification. Furthermore, the increase of flexibility of the LCP system and the use of titanium LCP could potentially promote uniform bone formation across the fracture gap, ultimately better healing outcomes.

The role of mechanical stimulation in the enhancement of bone healing.

The biomechanical environment plays a dominant role in the process of fracture repair. Mechanical signals control biological activities at the fracture site, regulate the formation and proliferation of different cell types, and are responsible for the formation of connective tissues and the consolidation of the fractured bone. The mechanobiology at the fracture site can be easily manipulated by the design and configuration of the fracture fixation construct and by the loading of the extremity (weight-bearing prescription). Depending on the choice of fracture fixation, the healing response can be directed towards direct healing or towards indirect healing through callus formation. This manuscript summarizes the evidence from experimental studies and clinical observations on the effect of mechanical manipulation on the healing response. Parameters like fracture gap size, interfragmentary movement, interfragmentary strain, and axial and shear deformation will be explored with respect to their respective effects on fracture repair. Also, the role of externally applied movement on the potential enhancement on the fracture repair process will be explored. Factors like fracture gap size, type and amplitude of the mechanical deformation as well as the loading history and its timing will be discussed.

The effect of femoral bone tunnel configuration on tendon-bone healing in an anterior cruciate ligament reconstruction: An animal study.

ObjectivesTo compare the effect of femoral bone tunnel configuration on tendon-bone healing in an anterior cruciate ligament (ACL) reconstruction animal model.MethodsAnterior cruciate ligament reconstruction using the plantaris tendon as graft material was performed on both knees of 24 rabbits (48 knees) to mimic ACL reconstruction by two different suspensory fixation devices for graft fixation. For the adjustable fixation device model (Socket group; group S), a 5 mm deep socket was created in the lateral femoral condyle (LFC) of the right knee. For the fixed-loop model (Tunnel group; group T), a femoral tunnel penetrating the LFC was created in the left knee. Animals were sacrificed at four and eight weeks after surgery for histological evaluation and biomechanical testing.ResultsHistologically, both groups showed a mixture of direct and indirect healing patterns at four weeks, whereas only indirect healing patterns were observed in both groups at eight weeks. No significant histological differences were seen between the two groups at four and eight weeks in the roof zone (four weeks, S: mean 4.8 sd 1.7, T: mean 4.5 sd 0.5, p = 0.14; eight weeks, S: mean 5.8 sd 0.8, T: mean 4.8 sd 1.8, p = 0.88, Mann-Whitney U test) or side zone (four weeks, S: mean 5.0 sd 1.2, T: mean 4.8 sd 0.4, p = 0.43; eight weeks, S: mean 5.3 sd 0.8,T: mean 5.5 sd 0.8, p = 0.61, Mann-Whitney U test) . Similarly, no significant difference was seen in the maximum failure load between group S and group T at four (15.6 sd 9.0N and 13.1 sd 5.6N) or eight weeks (12.6 sd 3.6N and 17.1 sd 6.4N, respectively).ConclusionRegardless of bone tunnel configuration, tendon-bone healing after ACL reconstruction primarily occurred through indirect healing. No significant histological or mechanical differences were observed between adjustable and fixed-loop femoral cortical suspension methods.Cite this article: Y. Sato, R. Akagi, Y. Akatsu, Y. Matsuura, S. Takahashi, S. Yamaguchi, T. Enomoto, R. Nakagawa, H. Hoshi, T. Sasaki, S. Kimura, Y. Ogawa, A. Sadamasu, S. Ohtori, T. Sasho. The effect of femoral bone tunnel configuration on tendon-bone healing in an anterior cruciate ligament reconstruction: An animal study. Bone Joint Res 2018;7:327–335. DOI: 10.1302/2046-3758.75.BJR-2017-0238.R2.

Changes in Serum Level of Vitamin D During Healing of Tibial and Femoral Shaft Fractures.

Dear Editor, We read with interest the article by Ettehad et al. (1), in which the authors provide a detailed discussion of the variations in serum vitamin D levels during the course of fracture healing. We have a few considerations regarding this study. The authors have not mentioned the treatment modalities used for these fractured limbs. Operatively managed fractures are mobilized early; consequently, the serum vitamin D levels of an ambulatory person may differ from those of a bedridden person. Ambulatory persons are also more likely to be exposed to sunlight, and vitamin D 3 (cholecalciferol) is synthesized by the human skin on exposure to the ultraviolet-B radiation of sunlight (2). Both dietary intake and endogenous synthesis contribute to the body’s vitamin D status. Since different factors modulate the extent of endogenous vitamin D formation, quantification is hardly possible. Regarding the objective of this study, the authors mentioned studying the role of vitamin D supplementation in the process of bone formation. However, they have not mentioned whether vitamin D supplementation was started in these patients. In addition, no mention is made regarding the effects of the low measured vitamin D levels on the final results of fracture healing. Tibia and femoral fractures take a longer time to unite, (3), so the serum vitamin D levels at the time of fracture union (i.e., six months and/or at the time of delayed union/non-union) should have been reported to make the study more effective. The levels of vitamin D showed uniform decreases in all age groups and among both genders in the first week, indicating that the fracture healing takes the same course (direct or indirect healing). All persons with fractured bones may not be targets for vitamin D supplementation, and only patients with previously low levels or patients with refractures might benefit from these supplementations (4). Further studies are required to determine the effect of low initial levels of vitamin D on fracture healing. The authors should expand on the present study by checking the levels of vitamin D at the time of radiological or clinical union of the fractures and then checking the effect of vitamin D supplementation on the fracture healing process. Furthermore, refracture in these patients may be an eye opener for developing countries, where we often see hypovitaminosis in the general populations.

L’osteogenesi riparativa

Bone healing of diaphyseal fractures is a complex biological process that involves different pathways. Direct healing needs rigid internal fixation, whereas indirect healing occurs in relative stability fixation techniques. There are many biological and mechanical factors that may influence the healing process. In order to provide the best treatment for each fracture, full knowledge of these factors is mandatory for the orthopaedic surgeon.

Do bisphosphonates inhibit direct fracture healing?

Fracture repair occurs by two broad mechanisms: direct healing, and indirect healing with callus formation. The effects of bisphosphonates on fracture repair have been assessed only in models of indirect fracture healing. A rodent model of rigid compression plate fixation of a standardised tibial osteotomy was used. Ten skeletally mature Sprague-Dawley rats received daily subcutaneous injections of 1 µg/kg ibandronate (IBAN) and ten control rats received saline (control). Three weeks later a tibial osteotomy was rigidly fixed with compression plating. Six weeks later the animals were killed. Fracture repair was assessed with mechanical testing, radiographs and histology. The mean stress at failure in a four-point bending test was significantly lower in the IBAN group compared with controls (8.69 Nmm(-2) (sd 7.63) vs 24.65 Nmm(-2) (sd 6.15); p = 0.017). On contact radiographs of the extricated tibiae the mean bone density assessment at the osteotomy site was lower in the IBAN group than in controls (3.7 mmAl (sd 0.75) vs 4.6 mmAl (sd 0.57); p = 0.01). In addition, histological analysis revealed progression to fracture union in the controls but impaired fracture healing in the IBAN group, with predominantly cartilage-like and undifferentiated mesenchymal tissue (p = 0.007). Bisphosphonate treatment in a therapeutic dose, as used for risk reduction in fragility fractures, had an inhibitory effect on direct fracture healing. We propose that bisphosphonate therapy not be commenced until after the fracture has united if the fracture has been rigidly fixed and is undergoing direct osteonal healing.

The biology of fracture healing

The biology of fracture healing is a complex biological process that follows specific regenerative patterns and involves changes in the expression of several thousand genes. Although there is still much to be learned to fully comprehend the pathways of bone regeneration, the over-all pathways of both the anatomical and biochemical events have been thoroughly investigated. These efforts have provided a general understanding of how fracture healing occurs. Following the initial trauma, bone heals by either direct intramembranous or indirect fracture healing, which consists of both intramembranous and endochondral bone formation. The most common pathway is indirect healing, since direct bone healing requires an anatomical reduction and rigidly stable conditions, commonly only obtained by open reduction and internal fixation. However, when such conditions are achieved, the direct healing cascade allows the bone structure to immediately regenerate anatomical lamellar bone and the Haversian systems without any remodelling steps necessary. In all other non-stable conditions, bone healing follows a specific biological pathway. It involves an acute inflammatory response including the production and release of several important molecules, and the recruitment of mesenchymal stem cells in order to generate a primary cartilaginous callus. This primary callus later undergoes revascularisation and calcification, and is finally remodelled to fully restore a normal bone structure. In this article we summarise the basic biology of fracture healing.

The contribution to the exact determination of biomechanochemical processes at indirect healing in callus after the distraction femoral osteotomy

The contribution to the exact determination of biomechanochemical processes at indirect healing in callus after the distraction femoral osteotomy

The biology of integration of the anterior cruciate ligament

The anterior cruciate ligament (ACL) is a short, stout, intra-articular, extrasynovial structure which acts to control rotational movements and anterior translation of the femur upon the fixed tibia.[1][1] Rupture is a traumatic event, often as a consequence of twisting upon the weight-bearing limb

Fixation of the graft in reconstruction of the anterior cruciate ligament

Methods of reconstruction of the anterior cruciate ligament (ACL) have developed considerably over the last 15 years. Primary repair and extra-articular procedures have failed to reproduce satisfactory stability of the knee[1][1] and the use of prosthetic ligaments has been abandoned.[2][2] These

Observations concerning different patterns of bone healing using the Point Contact Fixator (PC-Fix) as a new technique for fracture fixation

The recent trend in all surgical disciplines has been the development of techniques in minimally invasive surgery and the optimal maintenance of the blood supply to the bone fragments during osteosynthesis. Currently, the Point Contact Fixator (PC-Fix) has been introduced as a new implant for the stabilization of forearm bones. This plate-like splint and screw fixation system, which actually acts as an internal fixator, is characterized by minimized isolated contacts to the bone and proven angular stability of the monocortically locked screws. By using the PC-Fix, a further reduction of damage to the blood supply to the bone is achieved. Since 1994, 38 patients have been treated with this new device; we have reviewed the radiographs of 52 consolidated forearm fractures/osteotomies in accordance with the patterns of bone healing associated with the different methods of implant application according to the fracture type. In the groups in which traditionally precise reduction, interfragmentary compression and stable fixation was achieved (N=31), we found in 71% an absence of periosteal callus (direct bone healing). In the groups in which compression and adaptation were combined, or even main fragments adapted without compression, with wedges remaining unreduced in soft tissue connection (N=21), we found a visible external callus in 81% (indirect healing) (P = 0.002). Indirect healing after internal fixation is no longer regarded as a disturbance to healing, but is a goal in itself. The appearance of callus is a welcome sign indicating a prompt and positive reaction in the course of bone union which will lead to progressive fracture immobilization. When using the PC-Fix in a "biological way", callus formation and solid union take place earlier than in conventional plating. The new internal fixator offers substantial technical and mechanical advantages in fracture treatment. Therefore, it is an ideal implant to satisfy the requirements of modern biological osteosynthesis without compromising the restoration of axial alignment, rotation, length and postoperative functional treatment.

Clostridial collagenase releases bioactive fragments from extracellular matrix molecules.

The current study was designed to investigate the biological role of small extracellular matrix fragments in wound healing. Human burn eschar tissue was digested with bacterial collagenase, and small aminoacidic fragments were inoculated in both human dermal fibroblast cultures and polyvinyl alcohol sponges implanted subcutaneously in the rat. Proliferation assays on cell cultures and biochemical and histologic analyses of the animal model were then performed. Results showed that fibroblasts treated with low concentrations of eschar fragments duplicated significantly faster than controls. Biochemical and histologic data from sponge implants showed that the inflammatory response was augmented by eschar-derived fragments at postoperative day 2, whereas protein and hydroxyproline synthesis were decreased at day 14. In conclusion, these data substantiate that the application of bacterial collagenase to débride necrotic tissue may have an indirect healing effect resulting from the local release of bioactive matrix-derived fragments.

Healing of dentate or edentulous mandibular fractures treated with rigid or semirigid plate fixation — an experimental study in dogs

The right mandibles of 40 dogs were fractured with a bending clamp, at a site being either dentate or edentulous, and treated with compression-plates or miniplates. After 1, 2, 4, 6, 8, 12 and 24 weeks the mandibles were examined by microradiography and histology. Some variation in the healing mode within the groups was observed, interindividual as well as intra-individual in different layers of the same mandible. Generally, healing displayed slightly more time-related progression with compression plates compared with miniplates and similarly in dentate fracture sites when compared with edentulous ones. The so-called indirect healing mode through cartilaginous callus was found to take place in the group with miniplates and edentulous fracture sites, whereas in the three other groups a type of direct bone healing through woven bone in the presence of more or less callus could be observed. The conclusions drawn from these findings are: that compression plates as well as miniplates are suitable for treatment of mandibular fractures in dogs, and the presence of teeth appears to exert a stabilizing effect on the fracture.