Advances in the Application of Three-dimensional Printing for the Clinical Treatment of Osteoarticular Defects

As a promising manufacturing technology,three-dimensional(3D)printing technology is widely used in the medical field.In the treatment of osteoarticular defects,the emergence of 3D printing technology provides a new option for the reconstruction of functional articular surfaces.At present,3D printing technology has been used in clinical applications such as models,patient-specific instruments(PSIs),and customized implants to treat joint defects caused by trauma,sports injury,and tumors.This review summarizes the application status of 3D printing technology in the treatment of osteoarticular defects and discusses its advantages,disadvantages,and possible future research strategies.

Medical Additive Manufacturing: From a Frontier Technology to the Research and Development of Products

1.Research and development(R&D)and the challenges of raw materials for medical additive manufacturing Raw materials for medical additive manufacturing have a wide range of commonalities that are also seen in many other fields,making them an important basis in the field of three-dimensional(3D)printing.Problems and challenges related to material types,powder properties,formability,viscoelasticity,and so forth also share common features.For example,many metal materials are used in the field of aviation,while metals,polymers,and inorganic materials are used in the field of biomedicine.The most widely used materials in biomedicine are biocompatible.Various homogeneous and non-homogeneous composites are also available for 3D printing,and impose an additional challenge in additive manufacturing;the use of heterogeneous composites in 3D printing is particularly challenging.

Comparison and analysis of skiing injuries at ski resorts in Chongli,China and Japan

Purpose:The rapid development of winter sports requires investigation on injuries in Chongli district,Zhangjiakou city,one of the ski sites of the 2022 Winter Olympics.Careful evaluation is required to observe which injuries are caused under what circumstances,and then we can make corresponding preventive measures and recommendations based on the results.Methods:In this retrospective study,the data of injury cases at ski resorts in China(Chongli district)and Japan were analyzed to provide a reference for the ongoing injury prevention at ski resorts.We collected data on injuries at Wanlong and Fulong ski resorts in Chongli district during the 2017–2018 and 2018-2019 ski seasons.We referred to the skiing injury report issued in February 2020 of a nationwide ski safety statistical service–Japan Ski Safety Association.The causes of injury and specific injured body parts were analyzed based on the data of Chinese and Japanese ski resorts.Statistical significance has been calculated using the Chi-square test.Results:During the 2019–2020 ski season in Japanese ski resorts,the number of reported injuries per 10,000 skiers was 0.93,of which 457(17.3%)were over 50 years old,accounting for a large proportion of injuries,meanwhile in Chongli ski resort,the injury rate of skiers aged 50 and over was 7.1%.The knee joint(23.7%at Wanlong ski resort and 28.4%in Japanese ski resorts)was the most injured body part among Chongli and Japanese skiers.Among snowboarders,shoulder joint injury(17.7%in Japanese ski resorts)was the most common,and injury on hands and fingers(16.3%in Wanlong ski resorts)was the most common.Head injury rates are similar in Chongli,China and Japanese ski resorts(8.2%and 8.7%,respectively).Conclusion:Our analysis demonstrated that injury data recorded among young skiers was higher in Chinese ski resorts(Chongli district)than that in Japanese ski resorts,and elderly skiers made up a larger proportion of skiing injuries in Japanese resorts.Thus,according to our research,the protection of knee joints,shoulder joints,and hands and fingers should be taken seriously.It should pay attention to the teaching of ski poles(for finger protection),and use protective devices such as knee pads,helmets,etc.

Key considerations on the development of biodegradable biomaterials for clinical translation of medical devices:With cartilage repair products as an example

With the interdisciplinary convergence of biology,medicine and materials science,both research and clinical translation of biomaterials are progressing at a rapid pace.However,there is still a huge gap between applied basic research on biomaterials and their translational products-medical devices,where two significantly different perspectives and mindsets often work independently and non-synergistically,which in turn significantly increases financial costs and research effort.Although this gap is well-known and often criticized in the biopharmaceutical industry,it is gradually widening.In this article,we critically examine the developmental pipeline of biodegradable biomaterials and biomaterial-based medical device products.Then based on clinical needs,market analysis,and relevant regulations,some ideas are proposed to integrate the two different mindsets to guide applied basic research and translation of biomaterial-based products,from the material and technical perspectives.Cartilage repair substitutes are discussed here as an example.Hopefully,this will lay a strong foundation for biomaterial research and clinical translation,while reducing the amount of extra research effort and funding required due to the dissonance between innovative basic research and commercialization pipeline.

Full-thickness osteochondral defect repair using a biodegradable bilayered scaffold of porous zinc and chondroitin sulfate hydrogel

The regeneration of osteochondral tissue necessitates the re-establishment of a gradient owing to the unique characteristics and healing potential of the chondral and osseous phases.As the self-healing capacity of hyaline cartilage is limited,timely mechanical support during neo-cartilage formation is crucial to achieving optimal repair efficacy.In this study,we devised a biodegradable bilayered scaffold,comprising chondroitin sulfate(CS)hydrogel to regenerate chondral tissue and a porous pure zinc(Zn)scaffold for regeneration of the underlying bone as mechanical support for the cartilage layer.The photocured CS hydrogel possessed a compressive strength of 82 kPa,while the porous pure Zn scaffold exhibited a yield strength of 11 MPa and a stiffness of 0.8 GPa.Such mechanical properties are similar to values reported for cancellous bone.In vitro biological experiments demonstrated that the bilayered scaffold displayed favorable cytocompatibility and promoted chondrogenic and osteogenic differentiation of bone marrow stem cells.Upon implantation,the scaffold facilitated the simultaneous regeneration of bone and cartilage tissue in a porcine model,resulting in(i)a smoother cartilage surface,(ii)more hyaline-like cartilage,and(iii)a superior integration into the adjacent host tissue.Our bilayered scaffold exhibits significant potential for clinical application in osteochondral regeneration.

Effects of higher femoral tunnels on clinical outcomes,MRI,and second-look findings in double-bundle anterior cruciate ligament reconstruction with a minimal 5-year follow-up

Background:To perform anatomical anterior cruciate ligament reconstruction(ACLR),tunnels should be placed relatively higher in the femoral anterior cruciate ligament(ACL)footprint based on the findings of direct and indirect femoral insertion.But the clinical results of higher femoral tunnels(HFT)in double-bundle ACLR(DB-ACLR)remain unclear.The purpose was to investigate the clinical results of HFT and lower femoral tunnels(LFT)in DB-ACLR.Methods:From September 2014 to February 2016,83 patients who underwent DB-ACLR and met the inclusion and exclusion criteria were divided into HFT-ACLR(group 1,n=37)and LFT-ACLR(group 2,n=46)according to the position of femoral tunnels.Preoperatively and at the final follow-up,clinical scores were evaluated with International Knee Documentation Committee(IKDC),Tegner activity,and Lysholm score.The stability of the knee was evaluated with KT-2000,Lachman test,and pivot-shift test.Cartilage degeneration grades of the International Cartilage Repair Society(ICRS)were evaluated on magnetic resonance imaging(MRI).Graft tension,continuity,and synovialization were evaluated by second-look arthroscopy.Return-to-sports was assessed at the final follow-up.Results:Significantly better improvement were found for KT-2000,Lachman test,and pivot-shift test postoperatively in group 1(P>0.05).Posterolateral bundles(PL)showed significantly better results in second-look arthroscopy regarding graft tension,continuity,and synovialization(P<0.05),but not in anteromedial bundles in group 1.At the final follow-up,cartilage worsening was observed in groups 1 and 2,but it did not reach a stastistically significant difference(P>0.05).No statistically significant differences were found in IKDC subjective score,Tegner activity,and Lysholm score between the two groups.Higher return-to-sports rate was found in group 1 with 86.8%(32/37)vs.65.2%(30/46)in group 2(P=0.027).Conclusion:The HFT-ACLR group showed better stability results,better PL,and higher return-to-sports rate compared to the LFT-ACLR group.

Functional meniscus reconstruction with biological and biomechanical heterogeneities through topological self-induction of stem cells

Meniscus injury is one of the most common sports injuries within the knee joint,which is also a crucial pathogenic factor for osteoarthritis(OA).The current meniscus substitution products are far from able to restore meniscal biofunctions due to the inability to reconstruct the gradient heterogeneity of natural meniscus from biological and biomechanical perspectives.Here,inspired by the topology self-induced effect and native meniscus microstructure,we present an innovative tissue-engineered meniscus(TEM)with a unique gradient-sized diamond-pored microstructure(GSDP-TEM)through dual-stage temperature control 3D-printing system based on the mechanical/biocompatibility compatible high M_(w) poly(ε-caprolactone)(PCL).Biologically,the unique gradient microtopology allows the seeded mesenchymal stem cells with spatially heterogeneous differentiation,triggering gradient transition of the extracellular matrix(ECM)from the inside out.Biomechanically,GSDP-TEM presents excellent circumferential tensile modulus and load transmission ability similar to the natural meniscus.After implantation in rabbit knee,GSDP-TEM induces the regeneration of biomimetic heterogeneous neomeniscus and efficiently alleviates joint degeneration.This study provides an innovative strategy for functional meniscus reconstruction.Topological self-induced cell differentiation and biomechanical property also provides a simple and effective solution for other complex heterogeneous structure reconstructions in the human body and possesses high clinical translational potential.

Cryo-self-assembled silk fibroin sponge as a biodegradable platform for enzyme-responsive delivery of exosomes

Although advances in protein assembly preparation have provided a new platform for drug delivery during tissue engineering,achieving long-term controlled exosome delivery remains a significant challenge.Diffusion-dominated exosome release using protein hydrogels results in burst release of exosomes.Here,a fibroin-based cryo-sponge was developed to provide controlled exosome release.Fibroin chains can self-assemble into silk I structures under ice-cold conditions when annealed above the glass transition temperature.Exosome release is enzyme-responsive,with rates primarily determined by enzymatic degradation of the scaffolds.In vivo experiments have demonstrated that exosomes remain in undigested sponge material for two months,superior to their retention in fibrin glue,a commonly used biomaterial in clinical practice.Fibroin cryo-sponges were implanted subcutaneously in nude mice.The exosome-containing sponge group exhibited better neovascularization and tissue ingrowth effects,demonstrating the efficacy of this exosome-encapsulating strategy by realizing sustained release and maintaining exosome bioactivity.These silk fibroin cryo-sponges containing exosomes provide a new platform for future studies of exosome therapy.

Effects of visual restoration on gait performance and kinematics of lower extremities in patients with age-related cataract

Background:Visual inputs are critical for locomotor navigation and sensorimotor integration in the elderly;however,the mechanism needs to be explored intensively.The present study assessed the gait pattern after cataract surgery to investigate the effects of visual restoration on locomotion.Methods:The prospective study recruited 32 patients(70.1±5.2 years)with bilateral age-related cataracts in the Department of Ophthalmology at Peking University Third Hospital from October 2016 to December 2019.The temporal-spatial gait parameters and kinematic parameters were measured by the Footscan system and inertial measurement units.Paired t-test was employed to compare data normally distributed and Wilcoxon rank-sum test for non-normally distributed.Results:After visual restoration,the walking speed increased by 9.3%(1.19±0.40 m/s vs.1.09±0.34 m/s,P=0.008)and exhibited an efficient gait pattern with significant decrease in gait cycle(1.02±0.08 s vs.1.04±0.07 s,P=0.012),stance time(0.66±0.06 s vs.0.68±0.06 s,P=0.045),and single support time(0.36±0.03 s vs.0.37±0.02 s,P=0.011).High amplitude of joint motion was detected in the sagittal plane in the left hip(37.6°±5.3°vs.35.5°±6.2°,P=0.014),left thigh(38.0°±5.2°vs.36.4°±5.8°,P=0.026),left shank(71.9°±5.7°vs.70.1°±5.6°,P=0.031),and right knee(59.1°±4.8°vs.56.4°±4.8°,P=0.001).The motor symmetry of thigh improved from 8.35±5.30%to 6.30±4.73%(P=0.042).Conclusions:The accelerated gait in response to visual restoration is characterized by decreased stance time and increased range of joint motion.Training programs for improving muscle strength of lower extremities might be helpful to facilitate the adaptation to these changes in gait.

Chronic bilateral sleeve fracture of the patellae in a healthy child: a case report

To the Editor:Sleeve fracture of the patella is considered as a unique type of patellar injury to the pediatric population.It is a special type of avulsion fracture in which the avulsed fragment comprises of a small bony fragment from the patella,accompanied by a large portion of articular cartilage.[1]It makes up approximately half of patellar fracture in children.[2]However,the occurrence of this injury bilaterally is extremely rare and there has been only few reports regarding the treatment and prognosis to this injury during its chronic phase.Here we reported a case of chronic bilateral sleeve fracture of the patellae in a 13-year-old healthy boy,who got injured in a running competition.To the author’s best knowledge,this is the first case of chronic bilateral sleeve fracture of the patellae in current English literature.

A simplified noncryogenic strategy to transport mesenchymal stem cells: Potential applications in cell therapy and regenerative medicine

With the rapid advances in stem cell research and po-tential cell-based therapies,there is an urgent need to develop safe and reliable cell transport strategies.Except for autologous stem cell-based therapies,allogeneic stem cell therapies and ex vivo genetically engineered cell therapies would require safe,efficient,and reliable cell preservation and transport methods.

Sport medicine among the past three decades in China

In 1955,Professor Mianyu Qu,the founder of Chinese sports medicine,and the older generation of sports medicine practitioners,founded China’s sports medicine in response to the needs of the development of national sports and health.In therst 30 years of the establishment of sports medicine,they played an important role in the academic development,talent cultivation,international communication,construction of the society and organization,national Olympic glory,and nationaltness.Their contributions established a solid foundation for the rapid development of China’s sports medicine in the following 30 years.

The application of ECM-derived biomaterials in cartilage tissue engineering

Given the tremendous increase in the risks of cartilage defects in the sports and aging population,current treatments are limited,and new repair strategies are needed.Cartilage tissue engineering(CTE)is a promising approach to handle this burden and several fabrication technologies and biomaterials have been developed these years.The extracellular matrix(ECM)of cartilage consists of a tissue-specific 3D microenvironment with excellent biomechanical and biochemical properties,which regulates cell proliferation,adhesion,migration,and differentiation,thus attracting a great deal of attention to the rapid development of CTE based on ECM components.New generations of biomaterials are being developed rapidly for use as scaffolds to mimic the natural ECM environment.In this review,we discuss such CTE scaffolds based on ECM-derived biomaterials by reviewing the biomaterials for CTE,the applications in different scaffolds and their processing approaches,as well as the current clinical applications of those ECM-based CTE scaffolds.

Heterotopic ossification after arthroscopy for hip impingement syndrome

Background:Heterotopic ossification(HO)is a known complication of hip arthroscopy.We investigated incidence of HO after hip arthroscopy and determined whether revision for HO improved outcome.Methods:A retrospective study was conducted on 242 patients(140 men and 102 women,mean age:36.2±9.5 years)who underwent hip arthroscopy for femoroacetabular impingement(FAI)between January 2016 and January 2018.The average followup period was 22.88±11.74 months(range:11-34 months).Thirteen(5.37%)cases of HO(six men and seven women,five left hips and eight right hips;mean age:37.5±4.7 years)were observed.Among them,four cases with HO with obvious pain symptoms and persistent non-remission underwent revision surgery to remove HO.Monthly follow-up was conducted.Visual analog scale(VAS),modified Harris Hip Score(mHHS),and non-Arthritis Hip Score(NAHS)were evaluated and compared between HO and non-HO patients.Independent sample t test,Mann-Whitney U test and the Chi-square test were used for inter-group comparisons.HO degree was evaluated using Brooker classification.Symptoms and function were evaluated before and after revision.Results:A total of 242 patients were involved in this study.Thirteen cases(5.4%)had imaging evidence of HO.Nine(9/13)were classified as Brooker stageⅠ,three(3/13)Brooker stageⅡ,and one(1/13)Brooker stageⅢ.HO was detected by ultrasonography as early as 3 weeks after operation.After primary surgery,the mHHS of the HO group and non-HO group increased by 13.00(8.50,25.50)and 24.00(14.00,34.50)points(Z=-1.80,P=0.08),NAHS increased by 18.00(9.50,31.50)and 26.00(13.50,36.00)points(Z=-1.34,P=0.18),and VAS decreased by 3.00(2.00,4.00)and 4.00(3.00,4.50)points(Z=-1.55,P=0.12).Average follow-up time after revision was 9.00±2.94 months;mHHS increased by 34.75 points t=-55.23,P<0.01)and NAHS by 28.75 points t=-6.03,P<0.01),and VAS decreased by 4 points t=9.80,P<0.01).HO and non-HO patients were similar for demographic and surgical data,and clinical and functional scores.Conclusion:HO incidence after arthroscopic treatment of FAI is similar to that found in previous studies.Most HO have no effect on clinical symptoms.Patients who undergo revision HO resection show improvement in pain and joint function.

The neuropeptide CGRP enters the macrophage cytosol to suppress the NLRP3 inflammasome during pulmonary infection

The NLRP3 inflammasome plays an essential role in resistance to bacterial infection. The nervous system secretes multiple neuropeptides affecting the nervous system as well as immune cells. The precise impact of the neuropeptide CGRP on NLRP3 inflammasome activation is still unclear. Here, we show that CGRP negatively regulates the antibacterial process of host cells. CGRP prevents NLRP3 inflammasome activation and reduces mature IL-1β secretion. Following NLRP3 inflammasome stimulation that triggers endosome leakage, CGRP internalized to endosomal compartments is released into the cell cytosol. Cytosolic CGRP binds directly to NLRP3 and dismantles the NLRP3-NEK7 complex, which is crucial for NLRP3 inflammasome activation. CGRP administration exacerbates bacterial infection, while the treatment with a CGRP antagonist has the opposite effect. Our study uncovers a unique role of CGRP in inhibiting inflammasome activation during infections, which might shed new light on antibacterial therapies in the future.

An immunomodulatory polypeptide hydrogel for osteochondral defect repair

Osteochondral injury is a common and frequent orthopedic disease that can lead to more serious degenerative joint disease.Tissue engineering is a promising modality for osteochondral repair,but the implanted scaffolds are often immunogenic and can induce unwanted foreign body reaction(FBR).Here,we prepare a polypept(o)ide-based PAA-RGD hydrogel using a novel thiol/thioester dual-functionalized hyperbranched polypeptide P(EG3Glu-co-Cys)and maleimide-functionalized polysarcosine under biologically benign conditions.The PAA-RGD hydrogel shows suitable biodegradability,excellent biocompatibility,and low immunogenicity,which together lead to optimal performance for osteochondral repair in New Zealand white rabbits even at the early stage of implantation.Further in vitro and in vivo mechanistic studies corroborate the immunomodulatory role of the PAA-RGD hydrogel,which induces minimum FBR responses and a high level of polarization of macrophages into the immunosuppressive M2 subtypes.These findings demonstrate the promising potential of the PAA-RGD hydrogel for osteochondral regeneration and highlight the importance of immunomodulation.The results may inspire the development of PAA-based materials for not only osteochondral defect repair but also various other tissue engineering and bio-implantation applications.

Bioprinted constructs that simulate nerve-bone crosstalk to improve microenvironment for bone repair

Crosstalk between nerves and bone is essential for bone repair,for which Schwann cells(SCs)are crucial in the regulation of the microenvironment.Considering that exosomes are critical paracrine mediators for intercellular communication that exert important effects in tissue repair,the aim of this study is to confirm the function and molecular mechanisms of Schwann cell-derived exosomes(SC-exos)on bone regeneration and to propose engineered constructs that simulate SC-mediated nerve-bone crosstalk.SCs promoted the proliferation and differentiation of bone marrow mesenchymal stem cells(BMSCs)through exosomes.Subsequent molecular mechanism studies demonstrated that SC-exos promoted BMSC osteogenesis by regulating the TGF-βsignaling pathway via let-7c-5p.Interestingly,SC-exos promoted the migration and tube formation performance of endothelial progenitor cells.Furthermore,the SC-exos@G/S constructs were developed by bioprinting technology that simulated SC-mediated nerve-bone crosstalk and improved the bone regeneration microenvironment by releasing SC-exos,exerting the regulatory effect of SCs in the microenvironment to promote innervation,vascularization,and osteogenesis and thus effectively improving bone repair in a cranial defect model.This study demonstrates the important role and underlying mechanism of SCs in regulating bone regeneration through SC-exos and provides a new engineered strategy for bone repair.

SEMG-based fighter pilot muscle fatigue analysis and operation performance research

Fatigue has a tremendously adverse impact on pilot performance.This study aims to explore the Biceps Brachii(BB),Rectus Femoris(RF),Flexor Carpi Radialis(FCR),and Tibialis Anterior(TA)activities of fighter pilots in the early and late combat stages,and the target hitting time.A total of 13 volunteers were recruited to conduct simulated combats inside a real fighter cockpit.The surface Electromyography(sEMG)was collected from all volunteers in the initial and final 20s of flight,and the target hitting time during three simulated combats was recorded.The root mean square(RMS)values of right BB and TA were significantly higher than the left side values(p<0.001),while insignificant differences were found in the RMS values between the bilateral RF and FCR.Compared to the early flight period,the median frequency(MF)values of BB and TA were significantly lower during the late flight period,and the RMS values were significantly higher(p<0.047).Contrastively,the RMS values of FCR and RF differed insignificantly during the late flight period.Regarding the target hitting time,a significant difference was noted between task 1 and rask3.Subjects exhibit varying levels of muscle fatigue for different muscle groups before and after the flight.The muscle fatigue levels are asymmetrical on the left and right sides.Muscle fatigue might reduce the pilots'operational ability.This study provides a reference for fighter pilot fatigue protection and treatment.

使用细胞外基质启发的天然水凝胶支架促进骨软骨修复与透明软骨形成

骨软骨缺损是一个巨大的挑战,目前临床上尚未确定满意的修复策略.尤其是不恰当的修复方法可能导致纤维软骨和软骨下骨的生成,从而导致骨软骨组织的退化,最终导致修复失败.本研究受天然细胞外基质(extracellular matrix,ECM)中固有的化学成分的启发,提出了一种由天然多糖和多肽组成的新型仿生ECM支架,用于骨软骨修复.通过对天然生物聚合物进行修饰改性,形成具有可逆的客体-主体网络和刚性的共价网络的双网络结构,该支架不仅表现出优秀的生物相容性、细胞适应性和生物可降解性,还具有卓越的机械性能以适应骨软骨组织的环境.在兔的骨软骨缺损中,这种受ECM启发的支架不仅展示了强大的促进透明软骨形成的能力,还加速了具有优良骨密度的软骨下骨的再生.此外,新生的软骨和软骨下骨表现出了天然软骨的异质性特征,模拟了软骨到软骨下骨的渐进过渡.这些结果突显了该新型仿生ECM支架在临床应用中的潜在价值.

Loop changes after knee flexion-extension movement in a cadaveric anterior cruciate reconstruction model

Background:Recently,adjustable-loop devices(ALDs)have been widely used,and their reliability has always been the focus of attention.This study compared loop length changes under pull stress caused by flexion and extension of the cadaver knee between ALDs and fixed-loop devices(FLDs)in terms of femoral fixation after anterior cruciate ligament(ACL)reconstruction.Methods:ACL reconstruction in cadaveric knee joints was performed under arthroscopy with femoral suspension devices and tibial fixation by tying sutures on staples.The knee joint was repeatedly flexed and extended 30 times after fixation.According to the femoral fixation device used(Endobutton or Ultrabutton),the knee joints were divided into two groups:the ALD group(12 specimens)and the FLD group(ten specimens).The length of the loop before and after fixation was measured,and the loop length of the ALD group was re-measured 1 day after reconstruction.Results:There was no significant difference in the length of the loop between the two groups(t=0.579,P=0.569).One day later,the loop length of the ALDs retracted by 0.29±0.33(0–1.1)mm,and there was no retraction in three specimens.Conclusion:There was no significant difference in the loop length under flexion and extension stress after ACL reconstruction between ALDs and FLDs.