Interplay between mesenchymal stem cells and macrophages:Promoting bone tissue repair

The repair of bone tissue damage is a complex process that is well-orchestrated in time and space,a focus and difficulty in orthopedic treatment.In recent years,the success of mesenchymal stem cells(MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine.MSCs are closely related to macrophages.On one hand,MSCs regulate the immune regulatory function by influencing macrophages proliferation,infiltration,and phenotype polarization,while also affecting the osteoclasts differentiation of macrophages.On the other hand,macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment.The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration.Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair,and will also provide a reference for further application of MSCs in other diseases.

Impact of tibial transverse transport in tissue regeneration and wound healing with perspective on diabetic foot ulcers

In this editorial,we comment on an article by Liao et al published in the current issue of the World Journal of Diabetes.We focus on the clinical significance of tibial transverse transport(TTT)as an effective treatment for patients with diabetic foot ulcers(DFU).TTT has been associated with tissue regeneration,improved blood circulation,reduced amputation rates,and increased expression of early angiogenic factors.Mechanistically,TTT can influence macrophage polarization and growth factor upregulation.Despite this potential,the limitations and conflicting results of existing studies justify the need for further research into its optimal application and development.These clinical implications highlight the efficacy of TTT in recalcitrant DFU and provide lasting stimuli for tissue re-generation,and blood vessel and bone marrow improvement.Immunomodu-lation via systemic responses contributes to its therapeutic potential.Future studies should investigate the underlying molecular mechanisms to enhance our understanding and the efficacy of TTT.This manuscript emphasizes the potential of TTT in limb preservation and diabetic wound healing and suggests avenues for preventive measures against limb amputation in diabetes and peripheral artery disease.Here,we highlight the clinical significance of the TTT and its importance in healing DFU to promote the use of this technique in tissue regeneration.

A Review on the 3D Printing of Functional Structures for Medical Phantoms and Regenerated Tissue and Organ Applications

Medical models, or ＂phantoms,＂ have been widely used for medical training and for doctor-patient interactions. They are increasingly used for surgical planning, medical computational models, algorithm verification and validation, and medical devices development. Such new applications demand high-fidelity, patient-specific, tissue-mimicking medical phantoms that can not only closely emulate the geometric structures of human organs, but also possess the properties and functions of the organ structure. With the rapid advancement of three-dimensional （3D） printing and 3D bioprinting technologies, many researchers have explored the use of these additive manufacturing techniques to fabricate functional medical phantoms for various applications. This paper reviews the applications of these 3D printing and 3D bioprinting technologies for the fabrication of functional medical phantoms and bio-structures. This review specifically discusses the state of the art along with new developments and trends in 3D printed functional medical phantoms （i.e., tissue-mimicking medical phantoms, radiologically relevant medical phantoms, and physiological medical phantoms） and 3D bio-printed structures （i.e., hybrid scaffolding materials, convertible scaffolds, and integrated sensors） for regenerated tissues and organs.

Embedding aligned nanofibrous architectures within 3D-printed polycaprolactone scaffolds for directed cellular infiltration and tissue regeneration

Three-dimensional(3D) printing provides a promising way to fabricate biodegradable scaffolds with designer architectures for the regeneration of various tissues.However,the existing3D-printed scaffolds commonly suffer from weak cell-scaffold interactions and insufficient cell organizations due to the limited resolution of the 3D-printed features.Here,composite scaffolds with mechanically-robust frameworks and aligned nanofibrous architectures are presented and hybrid manufactured by combining techniques of 3D printing,electrospinning,and unidirectional freeze-casting.It was found that the composite scaffolds provided volume-stable environments and enabled directed cellular infiltration for tissue regeneration.In particular,the nanofibrous architectures with aligned micropores served as artificial extracellular matrix materials and improved the attachment,proliferation,and infiltration of cells.The proposed scaffolds can also support the adipogenic maturation of adipose-derived stem cells(ADSCs)in vitro.Moreover,the composite scaffolds were found to guide directed tissue infiltration and promote nearby neovascularization when implanted into a subcutaneous model of rats,and the addition of ADSCs further enhanced their adipogenic potential.The presented hybrid manufacturing strategy might provide a promising way to produce additional topological cues within 3D-printed scaffolds for better tissue regeneration.

Effects of regenerated tissue extracts after liver injury on the proliferation,differentiation,migration and invasion of SK-HEP1 cells

Objective: To study the effects of regenerated tissue extracts after liver injury on the proliferation, differentiation, migration and invasion of SK-HEP1 cells. Methods: Regenerated tissue extracts after liver injury were used to induce SK-HEP1 cells after enrichment, their effects on the proliferation, differentiation, migration and invasion of SK-HEPI cells were observed through in vitro cell culture, MTT, flow cytometry and transwell assays. Results:In response to the action of regenerated tissue extracts after liver injury, SK-HEP1 cells were blocked in G_0/G_1 phase, their growth rate was distinctly reduced. The number of SK-HEP1^(-fj)colonies decreased. The migration ability of SK-HEPI cells showed a decreased trend on day7 and day 11 after induction. SK-HEPl's invasion ability clearly decreased on days 7 and11 after induction, especially on day 7. Conclusions: To a certain extent, regenerated tissue extracts after liver injury can inhibit the proliferation, differentiation, migration and invasion of hepatoma cells, showing an important potential of being a differentiating agent for the treatment of liver cancer.

Combinatorial therapies for spinal cord injury repair

Spinal cord injuries have profound detrimental effects on individuals, regardless of whether they are caused by trauma or non-traumatic events. The compromised regeneration of the spinal cord is primarily attributed to damaged neurons, inhibitory molecules, dysfunctional immune response, and glial scarring. Unfortunately, currently, there are no effective treatments available that can fully repair the spinal cord and improve functional outcomes. Nevertheless, numerous pre-clinical approaches have been studied for spinal cord injury recovery, including using biomaterials, cells, drugs, or technological-based strategies. Combinatorial treatments, which target various aspects of spinal cord injury pathophysiology, have been extensively tested in the last decade. These approaches aim to synergistically enhance repair processes by addressing various obstacles faced during spinal cord regeneration. Thus, this review intends to provide scientists and clinicians with an overview of pre-clinical combinatorial approaches that have been developed toward the solution of spinal cord regeneration as well as update the current knowledge about spinal cord injury pathophysiology with an emphasis on the current clinical management.

Local icariin application enhanced periodontal tissue regeneration and relieved local inflammation in a minipig model of periodontitis

Periodontitis is an inflammatory autoimmune disease. Treatment should alleviate inflammation, regulate the immune reaction and promote periodontal tissue regeneration. Icariin is the main active ingredient of Epimedii Folium, and it is a promising compound for the enhancement of mesenchymal stem cell function, promotion of bone formation, inhibition of bone resorption, alleviation of inflammation and regulation of immunity. The study investigated the effect of icariin on periodontal tissue regeneration in a minipig model of periodontitis. The minipig model of periodontitis was established. Icariin was injected locally. The periodontal clinical assessment index, a computed tomography(CT) scan, histopathology and enzyme-linked immune sorbent assay(ELISA)were used to evaluate the effects of icariin. Quantitative analysis results 12 weeks post-injection demonstrated that probing depth,gingival recession, attachment loss and alveolar bone regeneration values were(3.72 ± 1.18) mm vs.(6.56 ± 1.47) mm,(1.67 ± 0.59)mm vs.(2.38 ± 0.61) mm,(5.56 ± 1.29) mm vs.(8.61 ± 1.72) mm, and(25.65 ± 5.13) mm3 vs.(9.48 ± 1.78) mm3 in the icariin group and0.9% NaCl group, respectively. The clinical assessment, CT scan, and histopathology results demonstrated significant enhancement of periodontal tissue regeneration in the icariin group compared to the 0.9% NaCl group. The ELISA results suggested that the concentration of interleukin-1 beta(IL-1β) in the icariin group was downregulated compared to the 0.9% NaCl group, which indicates that local injection of icariin relieved local inflammation in a minipig model of periodontitis. Local injection of icariin promoted periodontal tissue regeneration and exerted anti-inflammatory and immunomodulatory function. These results support the application of icariin for the clinical treatment of periodontitis.

Decellularized adipose matrix provides an inductive microenvironment for stem cells in tissue regeneration

Stem cells play a key role in tissue regeneration due to their self-renewal and multidirectional differentiation,which are continuously regulated by signals from the extracellular matrix(ECM)microenvironment.Therefore,the unique biological and physical characteristics of the ECM are important determinants of stem cell behavior.Although the acellular ECM of specific tissues and organs(such as the skin,heart,cartilage,and lung)can mimic the natural microenvironment required for stem cell differentiation,the lack of donor sources restricts their development.With the rapid development of adipose tissue engineering,decellularized adipose matrix(DAM)has attracted much attention due to its wide range of sources and good regeneration capacity.Protocols for DAM preparation involve various physical,chemical,and biological methods.Different combinations of these methods may have different impacts on the structure and composition of DAM,which in turn interfere with the growth and differentiation of stem cells.This is a narrative review about DAM.We summarize the methods for decellularizing and sterilizing adipose tissue,and the impact of these methods on the biological and physical properties of DAM.In addition,we also analyze the application of different forms of DAM with or without stem cells in tissue regeneration(such as adipose tissue),repair(such as wounds,cartilage,bone,and nerves),in vitro bionic systems,clinical trials,and other disease research.

Liver regeneration using decellularized splenic scaffold: a novel approach in tissue engineering

BACKGROUND： The potential application of decellularized liver scaffold for liver regeneration is limited by severe shortage of donor organs. Attempt of using heterograft scaffold is accompanied with high risks of zoonosis and immunological rejection. We proposed that the spleen, which procured more extensively than the liver, could be an ideal source of decellularized scaffold for liver regeneration. METHODS： After harvested from donor rat, the spleen was processed by 12-hour freezing/thawing ×2 cycles, then circulation perfusion of 0.02% trypsin and 3% Triton X-100 sequentially through the splenic artery for 32 hours in total to prepare decellularized scaffold. The structure and component characteristics of the scaffold were determined by hematoxylin and eosin and immumohistochemical staining, scanning electron microscope, DNA detection, porosity measurement, biocompatibility and cytocompatibility test. Recellularization of scaffold by 5×106 bone marrow mesenchymal stem cells（BMSCs） was carried out to preliminarily evaluate the feasibility of liver regeneration by BMSCs reseeding and differentiation in decellularized splenic scaffold.RESULTS： After decellularization, a translucent scaffold, which retained the gross shape of the spleen, was generated. Histological evaluation and residual DNA quantitation revealed the remaining of extracellular matrix without nucleus and cytoplasm residue. Immunohistochemical study proved the existence of collagens I, IV, fibronectin, laminin and elastin in decellularized splenic scaffold, which showed a similarity with decellularized liver. A scanning electron microscope presented the remaining three-dimensional porous structure of extracellular matrix and small blood vessels. The poros-ity of scaffold, aperture of 45.36±4.87 μm and pore rate of 80.14%±2.99% was suitable for cell engraftment. Subcutaneous implantation of decellularized scaffold presented good histocompatibility, and recellularization of the splenic scaffold demonstrated that BMSCs could locate and survive in the decellularized matrix. CONCLUSION： Considering the more extensive organ source and satisfying biocompatibility, the present study indicated that the three-dimensional decellularized splenic scaffold might have considerable potential for liver regeneration when combined with BMSCs reseeding and differentiation.

Three-dimensional printing of β-tricalcium phosphate/calcium silicate composite scaffolds for bone tissue engineering

Bioactive scaffolds with interconnected porous structures are essential for guiding cell growth and new bone formation. In this work, we successfully fabricated three-dimensional （3D） porous β-tricalcium phosphate （β-TCP）/calcium silicate （CS） composite scaffolds with different ratios by 3D printing technique and further investigated the physiochemical properties, in vitro apatite mineralization properties and degradability of porous β-TCP/CS scaffolds. Moreover, a series of in vitro cell experiments including the attachment, proliferation and osteogenic differentiation of mouse bone marrow stromal cells were conducted to testify their biological performances. The results showed that 3D printed β-TCP/CS scaffolds possessed of controllable internal porous structures and external shape. Furthermore, the introduction of CS decreased the shrinkage of scaffolds and improved the in vitro apatite formation activity and degradation rate. Meanwhile, compared with pure β- TCP scaffold, the β-TCP/CS composite scaffolds were more conducive to promote cell adhesion, spread and osteogenesis differentiation. However, when the content of CS was increased to 45%, the ions dissolution rate of the composite scaffolds was so high that leaded to the increase in pH value, which inhibited the proliferation of cells. Our results suggested that the introduction of appropriate CS into β-TCP bioceramic is an effective strategy to prepare bioactive 3D printed bioceramic scaffolds for hard tissue regeneration.

Targeted tissue engineering:hydrogels with linear capillary channels for axonal regeneration after spinal cord injury

Spinal cord injury（SCI）frequently results in the permanent loss of function below the level of injury due to the failure of axonal regeneration in the adult mammalian central nervous system（CNS）.The limited intrinsic growth capacity of adult neurons,a lack of growth-promoting factors and the multifactorial inhibitory microenvironment around the lesion site contribute to the lack of axonalregeneration. Strategies such as transplantation of cells,

Application of dental stem cells in three-dimensional tissue regeneration

Dental stem cells can differentiate into different types of cells.Dental pulp stem cells,stem cells from human exfoliated deciduous teeth,periodontal ligament stem cells,stem cells from apical papilla,and dental follicle progenitor cells are five different types of dental stem cells that have been identified during different stages of tooth development.The availability of dental stem cells from discarded or removed teeth makes them promising candidates for tissue engineering.In recent years,three-dimensional(3D)tissue scaffolds have been used to reconstruct and restore different anatomical defects.With rapid advances in 3D tissue engineering,dental stem cells have been used in the regeneration of 3D engineered tissue.This review presents an overview of different types of dental stem cells used in 3D tissue regeneration,which are currently the most common type of stem cells used to treat human tissue conditions.

Possible mechanism of 15D-PGJ2 in promoting periodontal tissue regeneration in patients with mandibular defects

Objective:To explore the main physiological mechanism of 15d-PGJ2 promoting periodontal tissue regeneration in patients with jaw defects caused by periodontal disease.Methods:From February 2016 to July 2019,a controlled study was conducted on 73 healthy residents(healthy group)and 73 patients(case group)with periodontal disease combined with jaw defects in Changsha medical university.T test was used to compare the growth factors of gingival crevicular fluid between the two groups.Peripheral blood cells;Cement-specific protein;Peripheral blood enzyme;Statistical differences in bone metabolites.The t test method compared the content of each index before and after treatment(15d-PGJ2 was treated at a dose of 200 mu/kg for 14 days).The method of factor analysis explores the internal correlation of each index.Result:RANKL,ICAM-1,TGF-β1,Th17,Treg,PDLSCs,SOST,CAP,HMGB1,CTSK,5-LOX,COX-2,NTX were higher in the case group than in the healthy group.In the case group,RANKL,ICAM-1,TGF-β1,Th17,Treg,PDLSCs,SOST,CAP,HMGB1,CTSK,5-LOX,COX-2,NTX were lower than those in the healthy group.The differences between the groups were statistically significant(P<0.05).Compared with before treatment,IL-1β,IL-17,Bfgf,YKL-40,BMP-2,ICTP,PICP,CTX were significantly decreased after treatment.RANKL,ICAM-1,TGF-β1,Th17,Treg,PDLSCs,SOST,CAP,HMGB1,CTSK,5-LOX,COX-2,NTX were significantly increased.The differences were statistically significant(P<0.05).Factor analysis shows that four common factors can be extracted from 21 indicators,and the cumulative contribution rate is 96.993%.Conclusions:The treatment of 15d-PGJ2 in patients with periodontal disease with maxillary defects can significantly affect the expression of multiple characteristic indicators,which may involve four mechanisms:dysregulation of cell differentiation or migration,local inflammation or immune imbalance,destruction of alveolar bone microstructure,load or stimulation,and remodeling.The specific pathway related to this is still to be further explored.

Research progress of strontium in promoting periodontal tissue regeneration

Periodontal disease is a chronic infectious disease of the oral cavity.Its main clinical features are periodontal pocket formation and alveolar bone resorption.Scholars'research hotspot is to achieve periodontal tissue regeneration in patients.Studies have found that strontium has certain potential in promoting periodontal tissue regeneration.In recent years,scholars have been conducting research on strontium and periodontal tissue regeneration,with a view to opening a new path for periodontal disease treatment.This article reviews the research status of strontium and periodontal tissue regeneration.The review results show that strontium can induce the proliferation and differentiation of PDLSCs and promote the regeneration of lost bone tissue;it can inhibit osteoclast activity and induce osteoclast apoptosis through a variety of signaling pathways,thereby inhibiting bone resorption;Promote bone formation;Strontium also has the function of promoting early angiogenesis and suppressing immune inflammatory response.Because the current research on strontium and periodontal tissue regeneration is only focused on in vivo and in vitro experiments,there is no relevant clinical trial to apply strontium to periodontal tissue regeneration.Therefore,if strontium is used to promote periodontal tissue regeneration to achieve the treatment of periodontal disease,further research is needed.

Nanofibrous scaffolds for the regeneration of nervous tissue

Introductons The biophysical organization of extracellular matrix (ECM) plays an important role in tissue morphogenesis,remodeling and functions. In many types of tissues,e. g. ,blood vessel,nerve,heart,muscle,tendon and ligament,ECM has aniso-

GUIDED TISSUE REGENERATION AROUND DENTAL IMPLANTS IN IMMEDIATE EXTRACTION SOCKETS:COMPARISON OF RESORBABLE ANDNONRESORBABLE MEMBRANES

This study was per formed to compare the efficacy of guided tissue regeneration (GTR) around dentalimplants immediately placed into extraction sockets by resorbable of nonresorbable membranes. Mandibular. P2, P3, and P4 of four aduIt beagle dogs were extracted bilaterally, and buccal standard defects were cre-ated and measured. Eighteen commercially pure titanium Steri-Oss implant fixtures were placed into thefresh extraction sockets. Four implants were untreated controls, four implants received polytetrafluoro-ethylene (e-PTFE, Gore-Tex) membranes, five implants received collagen membranes (ParaGuide), andfive implants received polyglactin 910 mesh (Vicryl). After l4 weeks, clinical measurements were takenand the dogs were sacrificed and all specimens retrieved for histologic and histomorphometric evaluation.The average gain in bone height was 2. 1mm for untreated control sites, 3. 3mm for Gore-Tex sites,3. 8mm for collagen sites, and 1. 3mm for polyglactin 910 sites. The greatest gain in bone height and volume was seen for two sites that received Gore-Tex membranes and remained covered for the entire evalua-tion interval. The results of this study indicate that Gore-Tex and collagen membrane preduced gdri re-sults for GTR around Implants immediately placed into extraction sockets. Since collagen membrane doesnot cause obvious infection and does not need the surgical reentry for membrane removal, it can be a validalternative to Gore-Tex membrane to improve bone regeneration around dental implants, while polyglactin910 mesh seems not suitable to be used as GTR membrane in immediate implantation for its hIgh infectionrate.

Cartilage and facial muscle tissue engineering and regeneration： a mini review

Cartilage and facial muscle tissue provide basic yet vital functions for homeostasis throughout the body, making human survival and function highly dependent upon these somatic components. When cartilage and facial muscle tissues are harmed or completely destroyed due to disease, trauma, or any other degenerative process, homeostasis and basic body functions consequently become negatively affected. Although most cartilage and cells can regenerate themselves after any form of the aforementioned degenerative disease or trauma, the highly specific characteristics of facial muscles and the specific structures of the cells and tissues required for the proper function cannot be exactly replicated by the body itself. Thus, some form of cartilage and bone tissue engineering is necessary for proper regeneration and function. The use of progenitor cells for this purpose would be very beneficial due to their highly adaptable capabilities, as well as their ability to utilize a high diffusion rate, making them ideal for the specific nature and functions of cartilage and facial muscle tissue. Going along with this, once the progenitor cells are obtained, applying them to a scaffold within the oral cavity in the affected location allows them to adapt to the environment and create cartilage or facial muscle tissue that is specific to the form and function of the area. The principal function of the cartilage and tissue is vascularization, which requires a specific form that allows them to aid the proper flow of bodily functions related to the oral cavity such as oxygen flow and removal of waste. Facial muscle is also very thin, making its reproduction much more possible. Taking all these into consideration, this review aims to highlight and expand upon the primary benefits of the cartilage and facial muscle tissue engineering and regeneration, focusing on how these processes are performed outside of and within the body.

Clinical trials using dental stem cells:2022 update

For nearly 20 years,dental stem cells(DSCs)have been successfully isolated from mature/immature teeth and surrounding tissue,including dental pulp of permanent teeth and exfoliated deciduous teeth,periodontal ligaments,dental follicles,and gingival and apical papilla.They have several properties(such as self-renewal,multidirectional differentiation,and immunomodulation)and exhibit enormous potential for clinical applications.To date,many clinical articles and clinical trials using DSCs have reported the treatment of pulpitis,periapical lesions,periodontitis,cleft lip and palate,acute ischemic stroke,and so on,and DSC-based therapies obtained satisfactory effects in most clinical trials.In these studies,no adverse events were reported,which suggested the safety of DSC-based therapy.In this review,we outline the characteristics of DSCs and summ-arize clinical trials and their safety as DSC-based therapies.Meanwhile,we also present the current limitations and perspectives of DSC-based therapy(such as harvesting DSCs from inflamed tissue,applying DSC-conditioned medi-um/DSC-derived extracellular vesicles,and expanding-free strategies)to provide a theoretical basis for their clinical applications.

Peripheral nerve regeneration through nerve conduits evokes differential expression of growth-associated protein-43 in the spinal cord

Growth-associated protein 43 plays a key role in neurite outgrowth through cytoskeleton remodeling.We have previously demonstrated that structural damage of peripheral nerves induces growth-associated protein 43 upregulation to promote growth cone formation.Conversely,the limited regenerative capacity of the central nervous system due to an inhibitory environment prevents major changes in neurite outgrowth and should be presumably associated with low levels of growth-associated protein 43 expression.However,central alterations due to peripheral nerve damage have never been assessed using the growthassociated protein 43 marker.In this study,we used the tubulization technique to repair 1 cm-long nerve gaps in the rat nerve injury/repair model and detected growth-associated protein 43 expression in the peripheral and central nervous systems.First,histological analysis of the regeneration process confirmed an active regeneration process of the nerve gaps through the conduit from 10 days onwards.The growth-associated protein 43 expression profile varied across regions and follow-up times,from a localized expression to an abundant and consistent expression throughout the regeneration tissue,confirming the presence of an active nerve regeneration process.Second,spinal cord changes were also histologically assessed,and no apparent changes in the structural and cellular organization were observed using routine staining methods.Surprisingly,remarkable differences and local changes appeared in growth-associated protein 43 expression at the spinal cord level,in particular at 20 days post-repair and beyond.Growth-associated protein 43 protein was first localized in the gracile fasciculus and was homogeneously distributed in the left posterior cord.These findings differed from the growth-associated protein 43 pattern observed in the healthy control,which did not express growth-associated protein 43 at these levels.Our results revealed a differential expression in growth-associated protein 43 protein not only in the regenerating nerve tissue but also in the spinal cord after peripheral nerve transection.These findings open the possibility of using this marker to monitor changes in the central nervous system after peripheral nerve injury.

Platelet rich fibrin is not a barrier membrane!Or is it?

Platelet-rich fibrin(PRF)is widely used in dentistry and other fields of medicine,and its use has become popular in dental implantology.In several published studies,PRF has been used as a barrier membrane.A barrier membrane is a sheet of a certain material that acts as a biological and mechanical barrier against the invasion of cells that are not involved in bone formation,such as epithelial cells.Among the basic requirements of a'barrier membrane,occlusivity,stiffness,and space maintenance are the criteria that PRF primarily lacks;therefore,it does not fall under the category of barrier membranes.However,there is evidence that PRF membranes are useful in significantly improving wound healing.Does the PRF membrane act as a barrier?Should we think of adding or subtracting some points from the ideal requirements of a barrier membrane,or should we coin a new term or concept for PRF that will incorporate some features of a barrier membrane and be a combination of tissue engineering and biotechnology?This review is aimed at answering the basic question of whether the PRF membrane should be considered a barrier membrane or whether it is something more beyond the boundaries of a barrier membrane.