Healing,Inflammation, and Fibrosis: Tendon: Principles of Healing and Repair

Tendon stores, releases, and dissipates energy to efficiently transmit contractile forces from muscle to bone. Tendon injury is exceedingly common, with the spectrum ranging from chronic tendinopathy to acute tendon rupture. Tendon generally develops according to three main steps: collagen fibrillogenesis, linear growth, and lateral growth. In the setting of injury, it also repairs and regenerates in three overlapping steps (inflammation, proliferation, and remodeling) with tendon-specific durations. Acute injury to the flexor and extensor tendons of the hand are of particular clinical importance to plastic surgeons, with tendon-specific treatment guided by the general principle of minimum protective immobilization followed by hand therapy to overcome potential adhesions. Thorough knowledge of the underlying biomechanical principles of tendon healing is required to provide optimal care to patients presenting with tendon injury.     

Healing,Inflammation, and Fibrosis: Wound Healing: A Comprehensive Review

Wound healing is an intricate, tightly regulated process that is critical to maintaining the barrier function of skin along with preserving all other skin functions. This process can be influenced by a variety of modifiable and nonmodifiable factors. As wound healing takes place in all parts of the human body, this review focuses on cutaneous wound healing and highlights the classical wound healing phases. Alterations in any of these phases can promote chronic wound development and may impede wound healing.     

Healing,Inflammation, and Fibrosis: Updates in Diabetic Wound Healing,Inflammation, and Scarring

Diabetic patients can sustain wounds either as a sequelae of their disease process or postoperatively. Wound healing is a complex process that proceeds through phases of inflammation, proliferation, and remodeling. Diabetes results in several pathological changes that impair almost all of these healing processes. Diabetic wounds are often characterized by excessive inflammation and reduced angiogenesis. Due to these changes, diabetic patients are at a higher risk for postoperative wound healing complications. There is significant evidence in the literature that diabetic patients are at a higher risk for increased wound infections, wound dehiscence, and pathological scarring. Factors such as nutritional status and glycemic control also significantly influence diabetic wound outcomes. There are a variety of treatments available for addressing diabetic wounds.     

CTRP3 Regulates Endochondral Ossification and Bone Remodeling During Fracture Healing

C1q/TNF-related protein 3 (CTRP3) is a cytokine known to regulate a variety of metabolic processes. Though previously undescribed in the context of bone regeneration, high throughput gene expression experiments in mice identified CTRP3 as one of the most highly upregulated genes in fracture callus tissue. Hypothesizing a positive regulatory role for CTRP3 in bone regeneration, we phenotyped skeletal development and fracture healing in CTRP3 knockout (KO) and CTRP3 overexpressing transgenic (TG) mice relative to wild-type (WT) control animals. CTRP3 KO mice experienced delayed endochondral fracture healing, resulting in abnormal mineral distribution, the presence of periosteal marrow compartments, and a nonunion-like state. Decreased osteoclast number was also observed in CTRP3 KO mice, whereas CTRP3 TG mice underwent accelerated callus remodeling. Gene expression profiling revealed a broad impact on osteoblast/osteoclast lineage commitment and metabolism, including arrested progression toward mature skeletal lineages in the KO group. A single systemic injection of CTRP3 protein at the time of fracture was insufficient to phenocopy the chronic TG healing response in WT mice. By associating CTRP3 levels with fracture healing progression, these data identify a novel protein family with potential therapeutic and diagnostic value. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:00-19966, 2020     

Cellular Mechanisms of Bone Repair

The extent of callus formation about a bone fracture depends on the rigidity of fracture fixation. The mechanism that converts the mechanical stimulus into the biologic response is unknown. On the basis of existing literature, an attempt has been made to define a model that explains this mechanobiologic transduction. Once integrity of the bone has been disrupted, a sequence of biochemical and cellular events commences that induces inflammatory reactions. Messengers (e.g., metabolites of the clotting or complement system, eicosanoids, or growth factors) are released or activated. They control the migration, proliferation, and protein synthesis of cells that are essential for angiogenesis and connective tissue formation. The key component in this inflammatory sequence seems to be the macrophage. Growth factors (e.g., released by macrophages) stimulate endothelial cells to form capillaries and mesenchymal cells to synthesize their matrix. In mechanically neutral areas, the fracture cavity is revascularized and osteoblasts proliferate and form bone. In mechanically instable fracture areas, spreading capillaries are disrupted by shear forces. In these areas, therefore, the milieu becomes hypoxic again. This milieu seems to support the differentiation of chondrocytes that stabilize the fracture by cartilage formation. If the strength of repair tissue is surpassed, the disrupture of the repair tissue triggers the mechanisms of inflammation again and additional cells immigrate and proliferate. Their protein synthesis increases repair callus. The increase of callus formation, however, stops when the tissue is capable of resisting motion. Links to the callus formation in osteitis are shown.     

Fracture Healing: A Concept of Competing Healing Factors

In the discussion concerning the theory of the healing of shaft fractures the demand for absolute stability of the fracture has been a dominating factor. This cannot be an absolute prerequisite because fractures of the tibia or femur heal well even with continued weight-bearing and movement. the ingrowth of vessels is apparently not a crucial factor. It is evident, however, that fractures caused by direct violence with soft tissue damage heal more slowly than fractures caused by indirect violence, irrespective of the treatment. Soft tissue heals with fibrous scar; fractures heal by bone regeneration. the author postulates that the damaged tissue stimulates (possibly via molecular determinants) the structural genes of undifferentiated cells to produce mRNA and proteins for either fibrous tissue or bone formation. the rate of healing of the fracture is determined by the degree of bone damage in relation to soft tissue damage. in fractures with extensive soft tissue injury there occurs a competitive condition in the common haematoma, with a risk of delayed fracture healing due to the dominance of cells that are triggered off by fibrous tissue formation.     

Fracture Healing: A Concept of Competing Healing Factors

In the discussion concerning the theory of the healing of shaft fractures the demand for absolute stability of the fracture has been a dominating factor. This cannot be an absolute prerequisite because fractures of the tibia or femur heal well even with continued weight-bearing and movement. the ingrowth of vessels is apparently not a crucial factor. It is evident, however, that fractures caused by direct violence with soft tissue damage heal more slowly than fractures caused by indirect violence, irrespective of the treatment. Soft tissue heals with fibrous scar; fractures heal by bone regeneration. the author postulates that the damaged tissue stimulates (possibly via molecular determinants) the structural genes of undifferentiated cells to produce mRNA and proteins for either fibrous tissue or bone formation. the rate of healing of the fracture is determined by the degree of bone damage in relation to soft tissue damage. in fractures with extensive soft tissue injury there occurs a competitive condition in the common haematoma, with a risk of delayed fracture healing due to the dominance of cells that are triggered off by fibrous tissue formation.     

Healing,Inflammation, and Fibrosis: Peripheral Nerve Healing: So Near and Yet So Far

Peripheral nerve injuries represent a considerable portion of chronic disability that especially affects the younger population. Prerequisites of proper peripheral nerve injury treatment include in-depth knowledge of the anatomy, pathophysiology, and options in surgical reconstruction. Our greater appreciation of nerve healing mechanisms and the development of different microsurgical techniques have significantly refined the outcomes in treatment for the past four decades. This work reviews the peripheral nerve regeneration process after an injury, provides an overview of various coaptation methods, and compares other available treatments such as autologous nerve graft, acellular nerve allograft, and synthetic nerve conduits. Furthermore, the formation of neuromas as well as their latest treatment options are discussed.     

唑来膦酸对老年桡骨远端骨折术后疗效观察

目的观察唑来膦酸对老年桡骨远端骨折的术后疗效。方法分析自2012年1月1日至2012年12月31日行桡骨远端骨折手术患者136例接受手术治疗并纳入研究,118例获得随访(87%),分成唑来膦酸组(A组,59例)和对照组(B组,59例)。唑来膦酸组平均年龄(73.09±5.04)岁,男12例,女47例,术后2~7 d使用唑来膦酸抗骨质疏松治疗,并常规补充钙剂和骨化三醇;对照组平均年龄(73.25±6.96)岁,男14例,女45例,术后2~7 d使用针剂密盖息抗骨质疏松治疗,出院后继续使用密盖息鼻喷剂至术后3个月,常规补充钙剂和骨化三醇,术后4周、3个月随访骨折愈合的情况及术后1年复查骨密度的情况。结果老年桡骨远端骨折患者使用唑来膦酸抗骨质疏松药物后骨折愈合无明显影响且腕关节功能改善,术后1年骨密度较前增加。结论发生桡骨远端骨折的老年骨质疏松患者使用唑来膦酸药物后骨质疏松治疗效果好,同时对骨质疏松性桡骨远端愈合无明显不利影响。     

Utilizing Multiple BioMEMS Sensors to Monitor Orthopaedic Strain and Predict Bone Fracture Healing

Current diagnostic modalities, such as radiographs or computed tomography, exhibit limited ability to predict the outcome of bone fracture healing. Failed fracture healing after orthopaedic surgical treatments are typically treated by secondary surgery; however, the negative correlation of time between primary and secondary surgeries with resultant health outcome and medical cost accumulation drives the need for improved diagnostic tools. This study describes the simultaneous use of multiple (n = 5) implantable flexible substrate wireless microelectromechanical (fsBioMEMS) sensors adhered to an intramedullary nail (IMN) to quantify the biomechanical environment along the length of fracture fixation hardware during simulated healing in ex vivo ovine tibiae. This study further describes the development of an antenna array for interrogation of five fsBioMEMS sensors simultaneously, and quantifies the ability of these sensors to transmit signal through overlaying soft tissues. The ex vivo data indicated significant differences associated with sensor location on the IMN (p < 0.01) and fracture state (p < 0.01). These data indicate that the fsBioMEMS sensor can serve as a tool to diagnose the current state of fracture healing, and further supports the use of the fsBioMEMS as a means to predict fracture healing due to the known existence of latency between changes in fracture site material properties and radiographic changes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1873–1880, 2019     

Healing,Inflammation, and Fibrosis: When Benign Becomes Cancer: Malignant Degeneration of Chronic Inflammation

Chronic inflammation, long implicated in the genesis of malignancy, is now understood to underlie an estimated 25% of all cancers. The most pertinent malignancies, to the plastic surgeon, associated with the degeneration of chronic inflammation include Marjolin''s ulcer, breast implant-associated large cell lymphoma, radiation-induced sarcoma, and Kaposi''s sarcoma. The cellular and genetic damage incurred by a prolonged inflammatory reaction is controlled by an increasingly understood cytokinetic system. Advances in understanding the chronic inflammatory cascade have yielded new therapeutics and therapeutic targets.     

Osteoporotic Animal Models of Bone Healing: Advantages and Pitfalls

The aim of this review was to summarize the advantages and pitfalls of the available osteoporotic animal models of bone healing. A thorough literature search was performed in MEDLINE via OVID and EMBASE to identify animal studies investigating the effect of experimental osteoporosis on bone healing and bone regeneration. The osteotomy model in the proximal tibia is the most popular osseous defect model to study the bone healing process in osteoporotic-like conditions, although other well-characterized models, such as the post-extraction model, might be taken into consideration by future studies. The regenerative potential of osteoporotic bone and its response to biomaterials/regenerative techniques has not been clarified yet, and the critical size defect model might be an appropriate tool to serve this purpose. Since an ideal animal model for simulating osteoporosis does not exist, the type of bone remodeling, the animal lifespan, the age of peak bone mass, and the economic and ethical implications should be considered in our selection process. Furthermore, the influence of animal species, sex, age, and strain on the outcome measurement should be taken into account. In order to make future studies meaningful, standardized international guidelines for osteoporotic animal models of bone healing need to be set up.     

The Effect of Nonsteroidal Anti-inflammatory Drugs and Selective COX-2 Inhibitors on Bone Healing

A recently published study, “Risk of Nonunion With Nonselective NSAIDs, COX-2 Inhibitors, and Opioids” by George et al (J Bone Joint Surg Am. 2020;102:1230–1238), assesses whether the use of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase 2 (COX-2) enzyme inhibitors, or opioids was associated with a risk of long bone fracture nonunion in Optum’s deidentified private health database. This review analyzes the study, including strengths, weaknesses, and areas for future research. The study found an association between COX-2 inhibitor and opioid use with fracture nonunion but not with nonselective NSAID use. Although the literature on this topic is varied, these results are at least partially aligned with several animal studies that show COX-2 inhibitors to be associated with fracture nonunion. The George et al study design has several important limitations, indicating that further research is needed on this topic.     

后外侧入路手术治疗三踝骨折的效果及对创面修复和骨折愈合速度的影响

目的 探讨后外侧入路手术治疗三踝骨折的效果及对创面和骨折愈合速度的影响。方法 选取2021年12月-2022年12月于合肥市骨科医院住院治疗的70例三踝骨折患者为研究对象,按照随机数字表法分为对照组和观察组,每组35例。对照组行传统入路手术治疗,观察组行后外侧入路手术治疗,比较两组手术相关指标、术后康复指标、踝关节功能恢复情况及切口美观满意度。结果 观察组手术持续时间短于对照组,术中出血量、术后引流量均低于对照组（P＜0.05）;观察组创面愈合时间、骨折愈合时间、住院时间均短于对照组（P＜0.05）;观察组踝关节功能优良率为88.57%,高于对照组的62.86%（P＜0.05）;观察组切口美观满意度（CS）评分高于对照组（P＜0.05）。结论 后外侧入路手术治疗三踝骨折的效果良好,可有效减少手术给患者带来的创伤,有利于缩短愈合时间及住院时间,改善踝关节功能,且患者的切口美观满意度较高。     

Bone Vascularization and Bone Healing in the Amputation Stump: An Experimental Study

The osseous healing process of the amputation stump was investigated in adult rabbits. Histological investigation showed that the medullary cavity was closed after 2-3 weeks, chiefly by endosteal callus. After closure of the cavity there was a gradual spongious change in the bone tip and simultaneously the cortex atrophied and the medullary cavity dilated. After amputation on the crus bone rebuilding dominated, whereas after amputation on the femur deterioration of bone was most noticeable. A combination of amputation and medullary plugging caused a change in the course of healing. The medullary cavity did not close until 7-10 weeks after operation and there was distinct periostea] callus formation.

The microangiographic investigation showed a transient hyper-vascularization in the cortex 3-4 weeks after amputation; whereas after simultaneous plugging of the medullary cavity the hypervasculari-zation continued for up to 7 weeks after operation. Following amputation proximally on the crus the arterial supply of the cortex came mainly from the periost, whereas the cortex after distal amputation was vascularized from the medullary cavity. This finding can be due to an interruption of the arterial supply from the nutrient artery associated with proximal amputation, whereas this artery remains intact with amputation distally on the crus.     

Advances and Promises of Nutritional Influences on Natural Bone Repair

Impaired fracture healing continues to be a significant public health issue. This is more frequently observed in aging populations and patients with co-morbidities that can directly influence bone repair. Tremendous progress has been made in the development of biologics to enhance and accelerate the healing process; however, side-effects persist that can cause significant discomfort and tissue damage. This has been the impetus for the development of safe and natural strategies to hasten natural bone healing. Of the many possible approaches, nutrition represents a safe, affordable, and non-invasive strategy to positively influence each phase of fracture repair. However, our understanding of how healing can be hindered by malnutrition or enhanced with nutritional supplementation has lagged behind the advancements in both surgical management and the knowledge of molecular and cellular drivers of skeletal fracture repair. This review serves to bridge this knowledge gap as well as define the importance of nutrition during fracture healing. The extant literature clearly indicates that pre-existing nutritional deficiencies should be corrected, and nutritional status should be carefully monitored to prevent the development of malnutrition for the best possible healing outcome. It remains unclear, however, whether the provision of nutrients beyond sufficiency has any benefit on fracture repair and patient outcomes. The combined body of pre-clinical studies using a variety of animal models suggests a promising role of nutrition as an adjuvant therapy to facilitate fracture repair, but extensive research is needed, specifically at the clinical level, to clarify the utility of nutritional interventions in orthopedics. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:695-707, 2020     

伤科接骨片对家兔骨折模型骨形态计量学动态参数的影响

目的：观察伤科接骨片对家兔骨折模型骨形态计量学动态参数的影响，探讨该药促进骨折愈合的机理。方法：36只雄性家兔行右侧桡骨骨缺损手术，造模成功的家兔随机分为空白对照组和伤科接骨片组，每组又随机分为3个亚组。术后第2d开始给药，连续用药至第11、21、35d分三批处死每亚组动物，取骨痂处骨组织制不脱钙骨切片，采用计算机半自动图像数字化分析仪测量骨组织形态计量学动态参数。结果：骨折愈合过程中在11d时伤科接骨片组荧光周长百分数和骨转换率均较空白对照组低（P＜0.05）；21d时伤科接骨片组荧光周长百分数和骨形成率均较空白对照组高（P＜0.05）；35d时骨形成率和骨转换率均较空白对照组低（P＜0.05），而伤科接骨片组软骨内成骨的骨计量学动态参数与空白对照组比较无明显差异（P＞0.05）。结论：伤科接骨片通过抑制骨折早期和中期膜内成骨的骨形成和骨转换，促进骨折中期膜内成骨的骨矿化和骨形成，而发挥其促进骨折愈合的作用。     

Bone formation, remodelling and healing

Bone is one of the largest organs in the body receiving 5-10% of the cardiac output. Bone formation starts early in the first trimester in utero and throughout life, it is continuously resorbed and formed, a process known as remodelling. Bone (fracture) healing is a process closely linked with both formation and remodelling. This article explores the basic structure of bone and provides the current understanding of intramembranous and endochondral bone formation, remodelling and primary and secondary bone healing.