28 research outputs found
Biodegradable magnesium implants, immunomodulation, and tissue repair/regeneration
Get PDFThe century-old paradigm of holding fractures with a metallic implant to enable bone repair, known as osteosynthesis, is still used today without alteration. Patients are increasingly being treated with metallic implants made of magnesium (Mg) that secure osteosynthesis and are reabsorbed in situ without the surgical re-entry that requires their permanent analogs. Often, Mg implants achieve osteosynthesis. However, when failure occurs, aberrant inflammation in overlaying soft tissue and persistent peri-implant radiolucencies generated by gas release from the implants are common. How can this be reconciled with popular concepts predestining Mg implants to promote bone formation by mitigating inflammation and bone resorption? This thesis investigated the sequence of biological processes prompting soft tissue and bone to accommodate Mg implants with different degradation behaviors from early to relatively long healing. Detailed studies of cells and their molecular circuits during inflammation were undertaken in different but related biological compartments surrounding the implants. Complementary analytical microscopy and compositional spectroscopy were performed to characterize tissue assembly at the interface with the implants and beyond. Compared to nondegradable titanium implants, Mg implants amplify initial inflammation in soft tissue and bone. The rapid release of degradation products, including Mg2+ and gas, correlatively induces a strong, transient proinflammatory environment that fosters mRNA and protein programs associated with macrophage polarization, chemotaxis, osteoclastogenesis, and neovascularization but without cytotoxic effects. Thereafter, inflammation markedly subsides. The transition to soft tissue and bone repair coincides with the attenuation of Mg2+ concentrations and gas void generation in the peri-implant milieu in tandem with an enrichment in calcium and phosphorous on the implant surface. Immunomodulation by Mg implants, reflected by a shift from proinflammatory to prohealing macrophage activation, reinforces their anchorage in bone and alleviates fibrotic encapsulation in soft tissue. However, this restorative effect is not equal in response to the various Mg degradation behaviors. Pure Mg implants, which degrade faster than clinical-grade alloyed Mg implants, alter the composition of interfacial bone and result in a previously unknown proadipogenic response in the bone marrow beyond the bone–implant interface. This increased adiposity is closely associated with persistent gas voids in bone marrow. Gas voids encourage inflammation in their microenvironment, trigger mechanosensation, and may induce local bone matrix deposition. In conclusion, Mg implants in different tissues transiently amplify the initial immune reaction, and degradation product escape creates an inflammatory microenvironment at the tissue–implant interface and beyond. An appropriate reparative response is obtained but can be impaired by the uncontrolled implant degradation. Above the demand for rigorous tailoring of Mg implants, healing monitoring needs to expand to tissues outside the confines of the implant interface, with pending questions on the fate of tissues under compromised conditions
Toward a disruptive, minimally invasive small finger joint implant concept: cellular and molecular interactions with materials in vivo
Get PDFOsteoarthritis (OA) poses significant therapeutic challenges, particularly OA that affects the hand. Currently available treatment strategies are often limited in terms of their efficacy in managing pain, regulating invasiveness, and restoring joint function. The APRICOT
Ⓡ implant system developed by Aurora Medical Ltd (Chichester, UK) introduces a minimally invasive, bone-conserving approach for treating hand OA (https://apricot-project.eu/). By utilizing polycarbonate urethane (PCU), this implant incorporates a caterpillar track-inspired design to promote the restoration of natural movement to the joint. Surface modifications of PCU have been proposed for the biological fixation of the implant. This study investigated the biocompatibility of PCU alone or in combination with two surface modifications, namely dopamine-carboxymethylcellulose (dCMC) and calcium-phosphate (CaP) coatings. In a rat soft tissue model, native and CaP-coated PCU foils did not increase cellular migration or cytotoxicity at the implant–soft tissue interface after 3 d, showing gene expression of proinflammatory cytokines similar to that in non-implanted sham sites. However, dCMC induced an amplified initial inflammatory response that was characterized by increased chemotaxis and cytotoxicity, as well as pronounced gene activation of proinflammatory macrophages and neoangiogenesis. By 21 d, inflammation subsided in all the groups, allowing for implant encapsulation. In a rat bone model, 6 d and 28 d after release of the periosteum, all implant types were adapted to the bone surface with a surrounding fibrous capsule and no protracted inflammatory response was observed. These findings demonstrated the biocompatibility of native and CaP-coated PCU foils as components of APRICOT
Ⓡ implants. Statement of significance: Hand osteoarthritis treatments require materials that minimize irritation of the delicate finger joints. Differing from existing treatments, the APRICOT
Ⓡ implant leverages polycarbonate urethane (PCU) for minimally invasive joint replacement. This interdisciplinary, preclinical study investigated the biocompatibility of thin polycarbonate urethane (PCU) foils and their surface modifications with calcium-phosphate (CaP) or dopamine-carboxymethylcellulose (dCMC). Cellular and morphological analyses revealed that both native and Ca-P coated PCU elicit transient inflammation, similar to sham sites, and a thin fibrous encapsulation in soft tissues and on bone surfaces. However, dCMC surface modification amplified initial chemotaxis and cytotoxicity, with pronounced activation of proinflammatory and neoangiogenesis genes. Therefore, native and CaP-coated PCU possess sought-for biocompatible properties, crucial for patient safety and performance of APRICOT
Ⓡ implant.</p
Biodegradable magnesium implants, immunomodulation, and tissue repair/regeneration
No full textThe century-old paradigm of holding fractures with a metallic implant to enable bone repair, known as osteosynthesis, is still used today without alteration. Patients are increasingly being treated with metallic implants made of magnesium (Mg) that secure osteosynthesis and are reabsorbed in situ without the surgical re-entry that requires their permanent analogs. Often, Mg implants achieve osteosynthesis. However, when failure occurs, aberrant inflammation in overlaying soft tissue and persistent peri-implant radiolucencies generated by gas release from the implants are common. How can this be reconciled with popular concepts predestining Mg implants to promote bone formation by mitigating inflammation and bone resorption? This thesis investigated the sequence of biological processes prompting soft tissue and bone to accommodate Mg implants with different degradation behaviors from early to relatively long healing. Detailed studies of cells and their molecular circuits during inflammation were undertaken in different but related biological compartments surrounding the implants. Complementary analytical microscopy and compositional spectroscopy were performed to characterize tissue assembly at the interface with the implants and beyond. Compared to nondegradable titanium implants, Mg implants amplify initial inflammation in soft tissue and bone. The rapid release of degradation products, including Mg2+ and gas, correlatively induces a strong, transient proinflammatory environment that fosters mRNA and protein programs associated with macrophage polarization, chemotaxis, osteoclastogenesis, and neovascularization but without cytotoxic effects. Thereafter, inflammation markedly subsides. The transition to soft tissue and bone repair coincides with the attenuation of Mg2+ concentrations and gas void generation in the peri-implant milieu in tandem with an enrichment in calcium and phosphorous on the implant surface. Immunomodulation by Mg implants, reflected by a shift from proinflammatory to prohealing macrophage activation, reinforces their anchorage in bone and alleviates fibrotic encapsulation in soft tissue. However, this restorative effect is not equal in response to the various Mg degradation behaviors. Pure Mg implants, which degrade faster than clinical-grade alloyed Mg implants, alter the composition of interfacial bone and result in a previously unknown proadipogenic response in the bone marrow beyond the bone–implant interface. This increased adiposity is closely associated with persistent gas voids in bone marrow. Gas voids encourage inflammation in their microenvironment, trigger mechanosensation, and may induce local bone matrix deposition. In conclusion, Mg implants in different tissues transiently amplify the initial immune reaction, and degradation product escape creates an inflammatory microenvironment at the tissue–implant interface and beyond. An appropriate reparative response is obtained but can be impaired by the uncontrolled implant degradation. Above the demand for rigorous tailoring of Mg implants, healing monitoring needs to expand to tissues outside the confines of the implant interface, with pending questions on the fate of tissues under compromised conditions
Autoinducer-2의 조절을 통한 복합감염원인의 실험적 치주염 완화
Get PDF학위논문 (석사)-- 서울대학교 대학원 : 치의학대학원 치의과학과, 2018. 2. 구기태.1. 연구목적
Quorum sensing(QS)이란 세포 간 통신 신호의 수집을 포함하는 명칭이다. QS 분자들은 세균의 다양한 중요한 기능, 예를 들면 영양소 획득, Redox 조절, 독성 등을 조절한다. 구강 바이오필름 내에선 Autoinducer-2 (AI-2) 라는 작은 QS 분자가 다양한 구강 세균에 의해서 만들어지는데, 이는 여러 종 간의 신호교환을 책임진다고 여겨진다. QS 억제제들은 Porphyromonas gingivalis 단독감염으로 치주염을 발생시킨 쥐 모델의 치은조직에서 박테리아의 집단형성과 뼈흡수를 방지시켰다. 그러나, AI-2 신호기전이 다양한 종에서 공통적이라는 점과 치주염을 유발시키는 다중미생물 감염에 의한 치주질환들을 고려했을때, 그 어떠한 자료도 바이오필름감염에 의한 치주염을 재현한 환경에서 다중감염원 억제제들의 효과를 밝히지 못했다.
이 연구의 우선적인 목적은 AI-2 의 억제를 통해서 in-vivo 환경에서 Porphyromonas gingivalis / Fusobacterium nucleatum 공동감염에 의한 치조골흡수를 완화할 수 있는지의 여부검사였다. 두번째로는, 같은 동물모델의 치주조직에서 AI-2 억제에 의한 세균감염과 염증반응을 평가하는 것이었다.
2. 연구방법
수컷 balb/c 쥐에서 42 일동안 6 번 P.gingivalis 와 F.nucleatum 를 구강 접종하여 치주염을 유도하였다. AI-2 억제제들인 BMK-101 과 D-ribose (QSIs)는 박테리아 감염과 동시에 주어졌다. Micro CT 를 사용해서 각 그룹 간 치간치조골의 직선적 및 용량적 변화를 측정하고 비교하였다. 치주조직에서 총 박테리아량, P. gingivalis, 그리고 전염증성 시토카인 유전자 발현량 등을 qRT PCR 을 통해서 측정했다.
3. 연구결과
직선적 측정결과를 통해 P. gingivalis 와 F. nucleatum 의 이중접종이 vehicle-접종된 쥐들보다 훨씬 더 심각한 뼈흡수를 보인 것을 확인하였다(p<0.01). 복합감염된 조직에 AI-2 억제제가 첨가되었을 때, 양성조절그룹에 비해서 치조골 흡수가 약 40%씩이나 감소된 것을 확인하였다 (p<0.05). 용량적 측정을 통해서는 감염되지 않은 쥐에 비해서 복합적감염이 뼈용량을 심각하게 감소시켰지만(p<0.01), QSI 투여를 통해서 예방된 것을
확인하였다(p<0.05). 뼈의 마이크로적 구성을 보았을때 한 면에선 trabecular number 가 treatment 그룹에서 positive control 그룹에서 보다 유의미하게 높았고 (p<0.05), 다른 면에선 trabecular separation 이 treatment 그룹에서 positive control 에 비해 낮아진 것을 확인하였는데(p<0.05) 이는 QSI 그룹이 치조골흡수 예방한다는 것을 지지했다. qRT PCR 결과에 따르면, QSI 가 조직에 추가되었을 때 treatment 그룹에서 모든 박테리아의 총량이 93%나 준 반면(p<0.05), 치주조직에서 P. gingivalis 의 양이나 전염증성 시토카인 유전자 발현량은 그룹 간 큰 차이를 보이지 않았다.
4. 결 론
단독감염 모델에서와 유사하게, AI-2 를 교환하는 다수의 치주질환균이 발생시킨 치주염도 AI-2 신호교환을 조절하므로써 완화시킬 수 있었다. 이 실험의 가장 큰 수확은 새로운 furanose compounds 인 BMK-Q101 와 Dribose 가 첨가되었을 때 치조골소실이 준 것을 확인한 것이다. AI-2 조절이 가지는 효과에 대한 강력한 증거는 아직 부족하다. AI-2 억제가 in-vivo 환경에서 바이오필름에 미치는 직접적인 영향은 연구되어야 하고 숙주반응의 변화와 연관되어져야 할 것이다.1. Objectives
Autoinducer-2 (AI-2) is a small quorum sensing (QS) molecule produced by many oral bacteria, within oral biofilm suggesting that this molecule might be responsible for signal exchange in mixed species communities. QS inhibitors (QSIs) were demonstrated to prevent bone loss and the bacterial colonization of gingival tissues in a mouse model where periodontitis was induced by Porphyromonas gingivalis monoinfection.
The aim of the present study was to verify whether the inhibition of AI-2 could attenuate alveolar bone loss induced by Porphyromonas gingivalis / Fusobacterium nucleatum co-infection invivo from one side and to evaluate the effect of AI-2 inhibition on bacterial infection and inflammatory response in the periodontal tissues from another side.
2. Methods
Periodontitis was induced in male balb/c mice (n=30) through the oral inoculation of P.gingivalis and F.nucleatum 6 times during 42days. BMK-Q101 and D-ribose (QSIs) were AI-2 inhibitors that were administrated simultaneously with bacterial infection. Linear and volumetric modifications of interproximal alveolar bone levels were compared between groups through MicroCT. Total bacterial infection, P.gingivalis infection and pro-inflammatory cytokine gene expression in periodontal tissues were assessed with qRT PCR.
3. Results
Micro CT linear measurements showed a significant reduction of alveolar bone loss by approximately 40% in animals treated with QSIs when compared to the mono and co-infection groups (p<0.05). These findings were confirmed by volumetric measurements (p<0.05). While qRT PRC showed that total oral bacteria in the treatment group significantly decreased by 93% in gingival tissue samples when QSIs were administrated (p<0.05), no significant differences could be depicted in P.gingivalis infection and pro-inflammatory cytokine genes expression in periodontal tissues between groups.
4. Conclusion
The administration of (BMK-Q101) and D-ribose attenuated alveolar bone loss induced by mouse co-infection. Less total bacteria colonization was observed in gingival tissues from treated animals. Further studies on the direct effect of AI-2 inhibition on biofilm in in vivo conditions are needed.I. INTRODUCTION 1
II. MATERIALS AND METHODS 4
III. RESULTS 15
IV. DISCUSSION 26
V. CONCLUSIONS 34
VI. REFERENCES 35
국문초록 40Maste
Response to Comment: Gas Bubbles from\ua0Biodegradable\ua0Magnesium Implants Convey Mechanical Cues and Promote Immune Cell Stimulation
No full textAssociation of prosthetic features and peri‐implantitis: A cross‐sectional study
No full textObjective To identify the influence of prosthetic features through a comprehensive analysis with other known risk factors. Materials and methods A total of 169 patients (n = implants: 349) was retrospectively included in the present study. Peri-implantitis was diagnosed based on peri-implant bone loss and probing depth. Using radiographs taken 1 and 5 years following prosthesis insertion, the following features were determined: peri-implant marginal bone loss (MBL), emergence angle (EA), emergence profile (EP) and crown/implant ratio (CIR). The splinted position of prosthesis was also recorded. Multivariable generalized estimating equation was used to analyse the influence of each feature on the prevalence of peri-implantitis. The final prediction model was constructed by Cox proportional hazard regression analysis. Results The EA showed a significant correlation with MBL. A statistically greater prevalence of peri-implantitis was observed if EA >= 30 degrees, when EP is convex and in middle implant splinted with both mesial and distal adjacent implants in bone-level implant. A similar correlation was not observed in tissue-level implants. CIR had no significant effect on the prevalence of peri-implantitis. Conclusion Over-contoured implant prosthesis is a critical local confounder for peri-implantitis. The implant splinted to both mesial and distal adjacent implant has a higher risk of peri-implantitis.N
Achieving stomal continence with an ileal pouch and a percutaneous implant
No full textIn this study, a soft-tissue-anchored, percutaneous port used as a mechanical continence-preserving valve in reservoir ileo- and urostomies was functionally and morphologically evaluated in eight dogs. During follow-up, the skin failed to attach to the implant, but the intestine inside the stoma port appeared to be attached to the mesh. After reaching adequate reservoir volume, the urostomies were rendered continent by attaching a lid to the implant. The experiments were ended at different time intervals due to implant-related adverse events. In only one case did the histological evaluation reveal integration at both the implant-intestine and implant-skin interfaces, with a low degree of inflammation and the absence of bacterial colonisation. In the remaining cases, integration was not obtained and instead mucosal downgrowth and biofilm formation were observed. The skin-implant junction was characterised by the absence of direct contact between the epidermis and the implant. Varying degrees of epidermal downgrowth, granulation tissue formation, inflammatory cell infiltration and bacterial growth and biofilm formation were prominent findings. In contrast, the subcutaneously located anchor part of the titanium port was well integrated and encapsulated by fibrous tissue. These results demonstrate the opportunity to achieve integration between a soft-tissue-anchored titanium port, skin and intestine. However, predictable long-term function could not be achieved in these animal models due to implant- and non-implant-related adverse events. Unless barriers at both the implant-skin and implant-intestine junctions are created, epidermal and mucosal downward migration and biofilm formation will jeopardise implant performance
Healing kinetics of oral soft tissue wounds treated with recombinant epidermal growth factor: Translation from a canine model
No full textDissecting the sequential interaction between biodegradable magnesium implants and soft tissues in vivo
No full textMagnesium-based biomaterials are developed with the intention to enable tissue regeneration while being degraded under physiological conditions and eventually eliminated from the body. Once in contact with tissues, the biodegradability and the biocompatibility of magnesium implants (Mg) are governed by the direct interactions with their immediate milieu. The precise mechanisms through which the soft tissue micro-environment shapes the behaviour of Mg and the host-response remain elusive. Here, it is demonstrated that Mg degradation modulates the initial acute immune response and the subsequent fibrous encapsulation upon subcutaneous implantation in rats monitored at 1-, 3-, 6-, 14- and 28-days following surgery. In comparison to titanium implants (Ti), the initial profuse release of Mg degradation products activates pro-inflammatory pathways through increased recruitment of inflammatory cells to the soft tissue/implant interface and upregulation of pro-inflammatory genes, in parallel with a superior neo-angiogenesis and vascularization at Mg. After 6d, a shift in Mg degradation kinetics dissipates the initial pro-inflammatory response and facilitates the assembly of a comparatively thinner fibrous tissue capsule than around Ti. The reduction in the fibrous encapsulation around the Mg implant aligns with a superior expression of anti-fibrotic marker FOXO-1 at the tissue interface with Mg versus Ti. Mg induce an initial potent yet transient inflammatory response, which is associated with less adverse fibrous encapsulation after tissue healing. Tailoring Mg with controlled initial degradation appears to be crucial to enabling a successful coupling between inflammation and tissue repair during the early host response to Mg
Early-life cow-level risk factors for sole ulcers in primiparous dairy cows
No full textSole ulcers negatively affect cow welfare and production economy. Previous cases of sole ulcers increase the risk of new or recurrent cases, and prevention of sole ulcers during the first lactation may therefore have a long-term effect, also in later lactations. Until now, risk factors for sole ulcers in the first lactation, associated with the period before heifers calve for the first time, have not been investigated. This study evaluated early-life cow-level risk factors for sole ulcers at the first hoof trimming in the first lactation. Early-life risk factors were defined as risk factors associated with the period before a cow calves for the first time. A dataset including information about all hoof trimming recordings during the years 2020 to 2022, and information about individual cows, was retrieved from the Danish Cattle Database. The dataset included only primiparous cows, and only cows that were hoof trimmed at least once during the first lactation. Overall, 1.95% of 466,113 cows included in the study had sole ulcers at the first hoof trimming in the first lactation. Results from a logistic regression model demonstrated a statistically significant interaction between breed and age at first calving (grouped based on quartiles within breed). Overall, across breeds, odds ratios of sole ulcers at the first hoof trimming in the first lactation were generally approximately 0.5 in the first quartile of age at first calving, approximately 0.6 in the second quartile, and approximately 0.75 in the third quartile, compared with the fourth quartile within the same breed. Odds of sole ulcers were generally higher in Jersey and Danish Red Dairy cows, compared with Holstein. In conclusion, the odds of sole ulcers in the first lactation increased with increasing age at first calving, and was approximately twice as high in cows calving among the oldest 25% within a breed, compared with cows calving among the youngest 25%. Focus on early-life risk factors for sole ulcers may have a major influence on the occurrence of sole ulcers throughout the life of cows
