Computational modeling of human bone fracture healing affected by different conditions of initial healing stage

Abstract Background Bone healing process includes four phases: inflammatory response, soft callus formation, hard callus development, and remodeling. Mechanobiological models have been used to investigate the role of various mechanical and biological factors on bone healing. However, the effects of initial healing phase, which includes the inflammatory stage, the granulation tissue formation, and the initial callus formation during the first few days post-fracture, are generally neglected in such studies. Methods In this study, we developed a finite-element-based model to simulate different levels of diffusion coefficient for mesenchymal stem cell (MSC) migration, Young’s modulus of granulation tissue, callus thickness and interfragmentary gap size to understand the modulatory effects of these initial phase parameters on bone healing. Results The results quantified how faster MSC migration, stiffer granulation tissue, thicker callus, and smaller interfragmentary gap enhanced healing to some extent. However, after a certain threshold, a state of saturation was reached for MSC migration rate, granulation tissue stiffness, and callus thickness. Therefore, a parametric study was performed to verify that the callus formed at the initial phase, in agreement with experimental observations, has an ideal range of geometry and material properties to have the most efficient healing time. Conclusions Findings from this paper quantified the effects of the initial healing phase on healing outcome to better understand the biological and mechanobiological mechanisms and their utilization in the design and optimization of treatment strategies. It is also demonstrated through a simulation that for fractures, where bone segments are in close proximity, callus development is not required. This finding is consistent with the concepts of primary and secondary bone healing.

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Can Optimizing the Mechanical Environment Deliver a Clinically Significant Reduction in Fracture Healing Time?

Biomedicines ◽

10.3390/biomedicines9060691 ◽

2021 ◽

Vol 9 (6) ◽

pp. 691

Author(s):

Jan Barcik ◽

Devakara R. Epari

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Mechanical Stimulation ◽

Callus Formation ◽

Weight Bearing ◽

Healing Process ◽

Healing Time ◽

Mechanical Environment ◽

Clinically Significant ◽

The Impact

The impact of the local mechanical environment in the fracture gap on the bone healing process has been extensively investigated. Whilst it is widely accepted that mechanical stimulation is integral to callus formation and secondary bone healing, treatment strategies that aim to harness that potential are rare. In fact, the current clinical practice with an initially partial or non-weight-bearing approach appears to contradict the findings from animal experiments that early mechanical stimulation is critical. Therefore, we posed the question as to whether optimizing the mechanical environment over the course of healing can deliver a clinically significant reduction in fracture healing time. In reviewing the evidence from pre-clinical studies that investigate the influence of mechanics on bone healing, we formulate a hypothesis for the stimulation protocol which has the potential to shorten healing time. The protocol involves confining stimulation predominantly to the proliferative phase of healing and including adequate rest periods between applications of stimulation.

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Wound care in venous ulcers

Phlebology The Journal of Venous Disease ◽

10.1177/0268355513477015 ◽

2013 ◽

Vol 28 (1_suppl) ◽

pp. 79-85 ◽

Cited By ~ 26

Author(s):

G Mosti

Keyword(s):

Granulation Tissue ◽

Wound Care ◽

Healing Process ◽

Cochrane Review ◽

Healing Time ◽

Polyurethane Foams ◽

Wound Dressings ◽

Pressure Treatment ◽

Venous Ulcers ◽

Moist Environment

Wound dressings: ulcer dressings should create and maintain a moist environment on the ulcer surface. It has been shown that in an ulcer with a hard crust and desiccated bed, the healing process is significantly slowed and sometimes completely blocked so favouring infection, inflammation and pain. In contrast a moist environment promotes autolytic debridement, angiogenesis and the more rapid formation of granulation tissue, favours keratinocytes migration and accelerates healing of wounds. Apart from these common characteristics, wound dressings are completely different in other aspects and must be used according to the ulcer stage. In necrotic ulcers, autolytic debridement by means of hydrogel and hydrocolloids or with enzymatic paste is preferred. In case of largely exuding wounds alginate or hydrofibre are indicated. When bleeding occurs alginate is indicated due to its haemostatic power. Where ulcers are covered by granulation tissue, polyurethane foams are preferred. When infection coexists antiseptics are necessary: dressing containing silver or iodine with large antibacterial spectrum have proved to be very effective. In the epithelization stage polyurethane films or membranes, thin hydrocolloids or collagen based dressings are very useful to favour advancement of the healing wound edge. Despite these considerations, a Cochrane review failed to find advantages for any dressing type compared with low-adherent dressings applied beneath compression. Surgical debridement and grafting of wounds, negative wound pressure treatment: surgical and hydrosurgical debridement are indicated in large, necrotic and infected wounds as these treatments are able to get rid of necrotic, infected tissue very quickly in a single surgical session, thereby significantly accelerating wound bed preparation and healing time. Negative wound pressure treatment creating a negative pressure on ulcer bed is able to favour granulation tissue and shorten healing time. In case of hard-to-heal leg ulcers such as large, deep, infected and long-lasting venous ulcers, sharp debridement and skin grafting may favour and shorten ulcer healing.

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Evaluation of longitudinal time-lapsedin vivomicro-CT for monitoring fracture healing in mouse femur defect models

10.1101/692343 ◽

2019 ◽

Author(s):

Esther Wehrle ◽

Duncan C Tourolle né Betts ◽

Gisela A Kuhn ◽

Ariane C Scheuren ◽

Sandra Hofmann ◽

...

Keyword(s):

Fracture Healing ◽

Radiation Effects ◽

Callus Formation ◽

Healing Process ◽

Fracture Repair ◽

Micro Ct ◽

Micro Computed Tomography ◽

Healing Phase ◽

Longitudinal Imaging

AbstractLongitudinalin vivomicro-computed tomography (micro-CT) is of interest to non-invasively capture the healing process of individual animals in preclinical fracture healing studies. However, it is not known whether longitudinal imaging itself has an impact on callus formation and remodeling. In this study, a scan group received weekly micro-CT measurements (week 0-6), whereas controls were only scanned post-operatively and at week 5 and 6. Registration of consecutive scans using a branching scheme (bridged vs. unbridged defect) combined with a two-threshold approach enabled assessment of localized bone turnover and mineralization kinetics relevant for monitoring callus remodeling. Weekly micro-CT application did not significantly change any of the assessed callus parameters in the defect and periosteal volumes. This was supported by histomorphometry showing only small amounts of cartilage residuals in both groups, indicating progression towards the end of the healing period. Also, immunohistochemical staining of Sclerostin, previously associated with mediating adverse radiation effects on bone, did not reveal differences between groups.The established longitudinalin vivomicro-CT-based approach allows monitoring of healing phases in mouse femur defect models without significant effects of anesthesia, handling and radiation on callus properties. Therefore, this study supports application of longitudinalin vivomicro-CT for healing-phase-specific monitoring of fracture repair in mice.

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Gambaran Penyembuhan Tulang Sekunder pada Fraktur dengan Anatomical Reduction Fixation Tipe Plate and Screw di RSUP Prof. Dr. R. D. Kandou Periode 2019 – 2020

e-CliniC ◽

10.35790/ecl.v9i1.32120 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Monica B. Donsu ◽

Andreissanto C. Lengkong ◽

Rangga B. V. Rawung

Keyword(s):

General Hospital ◽

Bone Healing ◽

Callus Formation ◽

Radiographic Examination ◽

Age Group ◽

Anatomical Reduction ◽

Keywords Fracture ◽

Male Patients ◽

Using Data ◽

Secondary Bone Healing

Abstract: Theoretically, fractures fixed by anatomical reduction fixation will undergo direct bone healing without any callus formation. However, in some cases with anatomical reduction fixation show sceondary bone healing in radiographic examination. This study was aimed to obtain the profile of patients who had secondary bone healing in fractures fixed with anatomical reduction fixation at Prof. Dr. RD Kandou Central General Hospital Manado from 2019 to 2020, distribution of patients based on age, sex, and fracture location, as well as the patient's callus indexes. This was a retrospective and descriptive study using data at the Surgery Section, Radiology Section and the Medical Record Section of Prof. Dr. R. D. Kandou General Hospital Manado. The results showed that the incidence of secondary bone healing in fractures with anatomical reduction fixation was the highest in the 21 - 35 years age group (50%). The number of male patients was greater than of female patients. The location of most fractures was the lower limb. The most frequent callus index was 0.51-0.75, the highest was 0.8, and the lowest was 0.25. In conclusion, secondary bone healing in fractures with anatomical reduction fixation was more common in age group 21-35 years, males, and had callus index of 0.51-0.75.Keywords: fracture, secondary bone healing, callus Abstrak: Secara teori fraktur yang difiksasi secara anatomical reduction fixation akan mengalami penyembuhan tulang secara langsung tanpa pembentukan kalus. Dalam praktik klinis pada beberapa kasus terlihat adanya gambaran kalus pada pemeriskaan radiografi yang menggambarkan adanya penyembuhan tulang sekunder pada fraktur dengan anatomical reduction fixation. Penelitian ini bertujuan untuk mendapatkan profil pasien yang mengalami penyembuhan tulang sekunder pada fraktur dengan anatomical reduction fixation di RSUP Prof. Dr. R. D. Kandou periode 2019 sampai dengan 2020, distribusi pasien berdasarkan usia, jenis kelamin dan lokasi fraktur, serta indeks kalus pasien. Jenis penelitian ialah deskriptif retrospektif menggunakan data di Bagian Bedah, Bagian Radiologi, dan Bagian Rekam Medik RSUP Prof. Dr. R. D. Kandou Manado. Hasil penelitian mendapatkan bahwa angka kejadian penyembuhan tulang sekunder pada fraktur dengan anatomical reduction fixation tertinggi pada kelompok usia 21-35 tahun (50%). Jumlah pasien laki-laki lebih banyak daripada perempuan dan lokasi fraktur tersering ialah ekstremitas bawah. Indeks kalus tertinggi (0,8) dan indeks kalus terendah (0,25), dan yang terbanyak ialah 0,51-0,75. Simpulan penelitian ini ialah penyembuhan tulang sekunder pada fraktur dengan anatomical reduction fixation tertinggi pada kelompok usia 21-35 tahun, jenis kelamin laki-laki, dengan indeks kalus 0,51-075Kata kunci: fraktur, penyembuhan tulang sekunder, kalus

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Evaluation of longitudinal time-lapsed in vivo micro-CT for monitoring fracture healing in mouse femur defect models

Scientific Reports ◽

10.1038/s41598-019-53822-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Esther Wehrle ◽

Duncan C. Tourolle né Betts ◽

Gisela A. Kuhn ◽

Ariane C. Scheuren ◽

Sandra Hofmann ◽

...

Keyword(s):

Fracture Healing ◽

Radiation Effects ◽

Callus Formation ◽

Healing Process ◽

Fracture Repair ◽

Micro Ct ◽

Micro Computed Tomography ◽

Healing Phase ◽

Longitudinal Imaging

AbstractLongitudinal in vivo micro-computed tomography (micro-CT) is of interest to non-invasively capture the healing process of individual animals in preclinical fracture healing studies. However, it is not known whether longitudinal imaging itself has an impact on callus formation and remodeling. In this study, a scan group received weekly micro-CT measurements (week 0–6), whereas controls were only scanned post-operatively and at week 5 and 6. Registration of consecutive scans using a branching scheme (bridged vs. unbridged defect) combined with a two-threshold approach enabled assessment of localized bone turnover and mineralization kinetics relevant for monitoring callus remodeling. Weekly micro-CT application did not significantly change any of the assessed callus parameters in the defect and periosteal volumes. This was supported by histomorphometry showing only small amounts of cartilage residuals in both groups, indicating progression towards the end of the healing period. Also, immunohistochemical staining of Sclerostin, previously associated with mediating adverse radiation effects on bone, did not reveal differences between groups. The established longitudinal in vivo micro-CT-based approach allows monitoring of healing phases in mouse femur defect models without significant effects of anesthesia, handling and radiation on callus properties. Therefore, this study supports application of longitudinal in vivo micro-CT for healing-phase-specific monitoring of fracture repair in mice.

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Evaluation of Bone Healing Using Contrast-Enhanced Ultrasonography in Non-Operative Treatment of Tibial Fracture in a Puppy Dog

Animals ◽

10.3390/ani11020284 ◽

2021 ◽

Vol 11 (2) ◽

pp. 284

Author(s):

Francesco Macrì ◽

Vito Angileri ◽

Teresa Russo ◽

Maria Tomiko Russo ◽

Marco Tabbì ◽

...

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Tibial Fracture ◽

Callus Formation ◽

Color Doppler ◽

Healing Process ◽

Power Doppler ◽

Low Velocity ◽

Blood Flows ◽

Contrast Enhanced

A 10-month-old mixed-breed male dog was presented with an oblique tibial fracture. The dog was treated with a Robert Jones-like bandage as a conservative approach, and was subjected to X-ray, B-mode, Color Doppler and contrast-enhanced ultrasound (CEUS) examinations during the fracture healing, in order to assess bone hemodynamic changes. B-mode, Power Doppler and CEUS examinations of the fracture gap were performed at 7, 20, 35, and 50 days post-trauma. Quantitative analysis of CEUS and perfusion parameters were obtained. On CEUS, a steep incline in signal numbers was visible in fracture gap at 7 days with peaks at 35 days, after which the vascularization decreases gradually over the next days. In this study, CEUS provided important information on the early stages of the callus formation and on the healing of neighboring tissues, allowing recognition of a correct bone healing. Moreover, the number of vascular signals on CEUS was greater than that on Doppler images on the same day. This report showed the application of CEUS in controlling the fracture healing process. CEUS could be a method of monitoring the remedial processes, assessing the tibial fracture perfusion characterized by low-velocity, small-volume blood flows.

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Wound With Diabetes: Present Scenario And Future

Current Diabetes Reviews ◽

10.2174/1573399816666200703180137 ◽

2020 ◽

Vol 16 ◽

Author(s):

Kuldeep B. Pawar ◽

Shivani Desai ◽

Ramesh R. Bhonde ◽

Ritesh P. Bhole ◽

Atul A. Deshmukh

Keyword(s):

Wound Healing ◽

Blood Flow ◽

Healing Process ◽

Endocrine System ◽

Healing Time ◽

Special Focus ◽

Diabetic Wound ◽

Management Options ◽

And Migration ◽

Proliferation And Migration

: Diabetes is a chronic metabolic disorder of endocrine system characterized by increase in blood glucose level. Several factors such as pancreatic damage, oxidative stress, infection, genetic factor, obesity, liver dysfunction play a vital role in pathogenesis of diabetes which further lead to serious diabetic complications. Diabetic wound is one such complication where the wound formation occurs, especially due to pressure and its healing process is disrupted due to factors such as hyperglycemia, neuropathy, nephropathy, peripheral vascular disease, reduction of blood flow, atherosclerosis, impaired fibroblast. Process of wound healing is delayed due to different abnormalities like alteration in nitric oxide level, increase in aldose reductase, sorbitol and fructose. Therefore, diabetic wound requires more time to heal as compare to normal wound. Healing time is delayed in diabetic wound due to many factors such as stress, decreased oxygenation supply, infection, decreased blood flow, impaired proliferation and migration rate, impaired growth factor production, impaired keratinocytes proliferation and migration, and altered vascular endothelial mediators. The current treatment for diabetic wound includes wound patches, oxygenation therapy, hydrogel patches, gene therapy, laser therapy, and stem cell therapy. Medications with phytoconstituents is also one way to manage diabetic wound, but it is not more effective for quick healing. The objective of this review is to understand the potential of various management options which are available for diabetic wound, with a special focus on biological cells.

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OP0244 A PRECLINICAL TESTING TOOL: THE IN VITRO 3D FRACTURE GAP MODEL

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3546 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 154.1-154

Author(s):

M. Pfeiffenberger ◽

A. Damerau ◽

P. Hoff ◽

A. Lang ◽

F. Buttgereit ◽

...

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Inflammatory Markers ◽

Initial Phase ◽

Gap Model ◽

Osteogenic Markers ◽

Immunosuppressed Patients ◽

The Impact

Background:Approximately 10% of fractures lead to significant fracture healing disorders, with a tendency to further increase due to the aging population. Of note, especially immunosuppressed patients with ongoing inflammation show difficulties in the correct course of fracture healing leading to fracture healing disorders. Most notably, invading immune cells and secreted cytokines are considered to provide an inflammatory microenvironment within the fracture gap, primarily during the initial phase of fracture healing. Current research has the focus on small animal models, facing the problem of translation towards the human system. In order to improve the therapy of fracture healing disorders, we have developed a human cell-basedin vitromodel to mimic the initial phase of fracture healing adequately. This model will be used for the development of new therapeutic strategies.Objectives:Our aim is to develop anin vitro3D fracture gap model (FG model) which mimics thein vivosituation in order to provide a reliable preclinical test system for fracture healing disorders.Methods:To assemble our FG model, we co-cultivated coagulated peripheral blood and primary human mesenchymal stromal cells (MSCs) mimicking the fracture hematoma (FH model) together with a scaffold-free bone-like construct mimicking the bony part of the fracture gap for 48 h under hypoxic conditions (n=3), in order to reflect thein vivosituation after fracture most adequately. To analyze the impact of the bone-like construct on thein vitroFH model with regard to its osteogenic induction capacity, we cultivated the fracture gap models in either medium with or without osteogenic supplements. To analyze the impact of Deferoxamine (DFO, known to foster fracture healing) on the FG model, we further treated our FG models with either 250 µmol DFO or left them untreated. After incubation and subsequent preparation of the fracture hematomas, we evaluated gene expression of osteogenic (RUNX2,SPP1), angiogenic (VEGF,IL8), inflammatory markers (IL6,IL8) and markers for the adaptation towards hypoxia (LDHA,PGK1) as well as secretion of cytokines/chemokines using quantitative PCR and multiplex suspension assay, respectively.Results:We found via histology that both the fracture hematoma model and the bone-like construct had close contact during the incubation, allowing the cells to interact with each other through direct cell-cell contact, signal molecules or metabolites. Additionally, we could show that the bone-like constructs induced the upregulation of osteogenic markers (RUNX2, SPP1) within the FH models irrespective of the supplementation of osteogenic supplements. Furthermore, we observed an upregulation of hypoxia-related, angiogenic and osteogenic markers (RUNX2,SPP1) under the influence of DFO, and the downregulation of inflammatory markers (IL6,IL8) as compared to the untreated control. The latter was also confirmed on protein level (e.g. IL-6 and IL-8). Within the bone-like constructs, we observed an upregulation of angiogenic markers (RNA-expression ofVEGF,IL8), even more pronounced under the treatment of DFO.Conclusion:In summary, our findings demonstrate that our establishedin vitroFG model provides all osteogenic cues to induce the initial bone healing process, which could be enhanced by the fracture-healing promoting substance DFO. Therefore, we conclude that our model is indeed able to mimic correctly the human fracture gap situation and is therefore suitable to study the influence and efficacy of potential therapeutics for the treatment of bone healing disorders in immunosuppressed patients with ongoing inflammation.Disclosure of Interests:Moritz Pfeiffenberger: None declared, Alexandra Damerau: None declared, Paula Hoff: None declared, Annemarie Lang: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi., Timo Gaber: None declared

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Bone Regeneration Assessment of Polycaprolactone Membrane on Critical-Size Defects in Rat Calvaria

Membranes ◽

10.3390/membranes11020124 ◽

2021 ◽

Vol 11 (2) ◽

pp. 124

Author(s):

Ana Paula Farnezi Bassi ◽

Vinícius Ferreira Bizelli ◽

Tamires Mello Francatti ◽

Ana Carulina Rezende de Moares Ferreira ◽

Járede Carvalho Pereira ◽

...

Keyword(s):

Bone Regeneration ◽

Bone Healing ◽

Inflammatory Responses ◽

Blood Clot ◽

Healing Process ◽

Male Rats ◽

Control Group ◽

Collagen Membrane ◽

Large Area ◽

Rat Calvaria

Biomaterials for use in guided bone regeneration (GBR) are constantly being investigated and developed to improve clinical outcomes. The present study aimed to comparatively evaluate the biological performance of different membranes during the bone healing process of 8 mm critical defects in rat calvaria in order to assess their influence on the quality of the newly formed bone. Seventy-two adult male rats were divided into three experimental groups (n = 24) based on the membranes used: the CG—membrane-free control group (only blood clot, negative control), BG—porcine collagen membrane group (Bio-Guide®, positive control), and the PCL—polycaprolactone (enriched with 5% hydroxyapatite) membrane group (experimental group). Histological and histometric analyses were performed at 7, 15, 30, and 60 days postoperatively. The quantitative data were analyzed by two-way ANOVA and Tukey’s test (p < 0.05). At 7 and 15 days, the inflammatory responses in the BG and PCL groups were significantly different (p < 0.05). The PCL group, at 15 days, showed a large area of newly formed bone. At 30 and 60 days postoperatively, the PCL and BG groups exhibited similar bone healing, including some specimens showing complete closure of the critical defect (p = 0.799). Thus, the PCL membrane was biocompatible, and has the potential to help with GBR procedures.

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