This study examines the causal nexus between Foreign Direct Investment (FDI) and the economic growth of seven (7) regions encompassing 117 countries. A more recent panel dataset over the period 2010–2020 was analysed using the Granger causality approach and panel VAR/block exogeneity test to conduct predictive analysis among the panel series. Wavelet coherence techniques too were adapted in bringing novelty and further justifications to the research in exploring the interaction effects of the variables, which are yet to be popularised in the studied discipline. The empirical results indicate the presence of bi-directional causality between FDI and economic growth globally and in the Asian region. In contrast, the causality is uni-directional in the American region. A non-directional causality was discovered in European, Oceanian, Mediterranean, and African regions, and the findings were consistent with the outcome of the wavelet coherence technique results. The study further classifies the regions into three cross-market categories such as developed, emerging and frontier markets. The results imply no causality for most developed and emerging economies in the regional analysis. Findings also provide insights for governments and policymakers worldwide to formulate policies on directing FDI flows and propositions for a host country to become a more conducive destination for FDI and accelerate economic growth. Foreign capital, specifically Foreign Direct Investment (FDI), is surging worldwide due to the interconnection of national economies through international trade and capital transfers, boosting overall economic growth. This has been further fuelled by the rise of globalisation and amicable diplomatic ties nations have developed, in addition to well-connected financial markets. However, despite the extensive past literature on the relationship between FDI and economic growth in both developed and developing countries, conflicting results were observed throughout .According to Kalai and Zghidi  and BellThe interaction between FDI and economic growth has recently garnered considerable attention from researchers and policymakers in the host countries. Iamsiraroj and Ulubaşoğlu  provide Extant literature concludes the relationship to be uni-directional, bi-directional, or non-directional –10 in teWhilst the hitherto literature emphasises mixed results for the causality between FDI and economic growth, it also justifies the need for more detailed research in the subject domain. Though several studies have investigated the relationship between FDI and economic growth, the direction of causality between these variables is particularly under-examined, though it cannot be underrated. Moreover, it is crucial to examine the relationship between FDI and economic growth to identify whether FDI fueled the swift economic growth of the considered regions, or whether a reciprocal relationship existed between economic growth and FDI,—which was not sufficiently addressed in the extant literature.The study’s main objective is to verify the causal link between FDI and economic growth by capturing seven (07) regions and a more refined technical analysis.Consequently, the present study substantially contributes to the existing literature on five fronts: firstly, it investigates the causal relationship between FDI and economic growth across six regions and multiple countries in a global context using a more recent panel dataset that covers the period from 2010 to 2020; secondly, it deploys a bivariate Granger causality model and panel VAR/block exogeneity test on the acquired data, which has been proven to be superior to conventional panel data analysis approaches; thirdly, conducts an in-depth exploration of the dynamic causal relationship between FDI and economic growth for regions globally in recent years. The novelty of this study is that, to the best of the authors’ knowledge, it is the pioneer study done by local researchers that uses current panel data methodology to observe the causal relationship of the study variables across world regions. Fourthly, this is the first paper to bring the wavelet coherence technique that offers more intuitive understanding of the linkages between the considered variables signifying short-term or long-term reactions. This is yet to be popularised in the discipline of study, to further justify the interaction effects of the variables together with the Granger causality test, which improves the originality of the study. This will assist in understanding the direction of the causal relationship between these macroeconomic variables and aid the governments, stakeholders, private institutions, academic scholars, and policymakers in duly integrating their FDI policies into macroeconomic objectives for all-inclusive, sustainable economic growth and development. Fifthly, this study is the initial panel study to extensively examine the dynamic causal linkage between FDI, net inflows, and economic growth for regional cross-markets besides the comparative regional analysis and enables to understand the influence of cross-market differences on FDI and GDP within the scope of developed, emerging and frontier markets.The subsequent sections of this paper outline the empirical review of the literature followed by model specification, estimation approaches, analysis and discussion of the findings, and finally reaching the conclusions and policy implications.This study centred the literature review on 63 initially identified articles through a comprehensive and detailed literature search shown in The search strategy was divided into four parts, namely: (i) identification, (ii) screening, (iii) eligibility, and (iv) inclusion. In the identification step, several relevant papers were explored using keywords. Initially, out of 208 research papers shortlisted, 37 were excluded due to duplications. The researchers directed the remaining 171 papers to the screening stage and read and reviewed the abstracts of the research papers. The studies deemed to have insignificantly contributed or were unrelated to the selected topic were excluded resulting in 59 exclusions.The remaining 112 research papers were further screened in the eligibility step. The ABDC rank, Scopus, CiteScore, and Scimago H-index of journals pertaining to published papers were checked. The papers that have slight relevance to the topic and papers published in low-ranking journals were excluded resulting in 49 exclusions. Subsequently, the remaining articles were classified into three (03) main categories considering the relationship of main variables as bi-directional causality, uni-directional causality and non-directional causality.The selected 63 papers were further categorised into seven topics, namely global  and identified regions: Asian, African, American, European, Oceanian, and the Mediterranean. The literature pertaining to the relationship between FDI, and economic growth was discussed to establish a solid scientific background for the study. This section will present an extensive review of the literature to emphasise research findings related to this topic, identify their limitations and knowledge gaps and highlight the contribution of the research.According to the study by Mahembe and N , FDI conThe causal relationship between FDI and Gross Domestic Product (GDP) growth could move either way. According to McKinnon , the majThe causality could also move in the opposite direction; rapid GDP growth often results in a massive capital resource gap in a host nation. Since FDI is one of the main sources of capital , the hosThe latent literature consistently highlights three main conclusions on the relationship between FDI and economic growth; uni-directional, bi-directional, or non-directional. A discussion on the existing literature pertinent to the relationships of the main variables studied in this research is discussed region-wise henceforth.FDI flows grew dramatically globally in the last two decades. This is because many countries view FDI as a critical component of their respective economic growth strategies. Several studies consider the possible relationship between FDI and economic growth globally. Similarly, a study for 19 Eurozone countries by Pradhan, Arvin  and a stIamsiraroj and Ulubaşoğlu  performeA few studies conducted analysed FDI and economic growth in Africa. These revealed that FDI can be transformative for the region and is crucial for helping Africa towards long-term sustainability and economic growth.Using the Autoregressive Distributed Lag (ARDL) bounds testing approach and the Granger causality test, Owusu  examinedA few studies have concluded that the said causality is uni-directional in African countries. Mahembe and Odhiambo  found thMoreover, non-directionality between FDI and economic growth was observed in Africa as evidenced by Tekin  in his sThe causal relationship between FDI and economic growth requires much attention in the American region. Contemporary studies done by Al Nasser  and OwusContradicting the findings of these studies, Al Nasser  found a Furthermore, Naguib  and ChenA vast majority of empirical studies have focused on the effects exerted on economic growth along the causal link between FDI and economic growth. Palamalai Srinivasan, M. Kalaivani  found thTwo studies by Iqbal, Shaikh  and ChanContrary to these studies, some research papers have concluded that FDI and economic growth have a uni-directional causality in the Asian region. Hsiao and Hsiao  found a In addition, a Singaporean study by Akalpler and Adil  and a CaThe empirical evidence of the relationship between FDI and economic growth is inconclusive in the European region. Surprisingly, no study has found bi-directional causality between FDI and economic growth in Europe. However, Moudatsou  found thIn contrast to these studies, Nath  concludeDetermination of the causal patterns between FDI and economic growth has important implications for a developing region and the causality between FDI and economic growth in the Mediterranean region has been substantiated by numerous empirical studies.A study in Turkey done by Gunaydin and Tatoglu  and an IAsheghian  concludeIn the FDI-growth literature, empirical studies have so far yielded mixed results in the Oceanian region. Jayaraman and Choong  concludeBesides, Iyer, Rambaldi  proved tIn addition, some country-specific studies have identified potential determinants of FDI such as trade openness –80 markeHowever, these determinants have not been considered in this study due to the lack of data availability for some of the countries in the sample . Due to the higher sample size in the current study, it is unrealistic to encompass the stated determinants without obtaining blank values for several smaller economies.This study created a macro panel model for 117 countries; specifically, 28 African, 18 American, 34 Asian, 27 European, 5 Mediterranean, and 5 Oceanian countries were analysed. The research data are confined to the period in which annual data are collected for the period 2010 to 2020 from the World Development Indicators published by the World Bank. The data file used for the study is presented in The data utilised for the cross-market analysis covers 23 developed markets, 21 emerging markets and 16 frontier markets under separate regions, based on the Morgan Stanley Capital International market classification framework. The original sample size was reduced by considering the data availability. The list of countries used for the cross-market analysis is provided in The paneled variable, economic growth in terms of GDP per capita is obtained by dividing the mid-year population by the gross domestic output. GDP is calculated as the total gross value added by all resident producers in the economy, plus any product taxes, minus any subsidies not included in the product value. It is estimated without considering the depreciation of manufactured assets or natural resource depletion and degradation. All collected data are in current US$ .The other paneled variable, FDI net inflows, were taken as a percentage of GDP, where the FDI is defined as net inflows of funds used to acquire a long-term managerial stake (10% or more of voting stock) in a company that operates in a country other than the investors. The balance of payments represents the sum of equity capital, earnings reinvestment, other long-term and short-term capital. Data were extracted from , segmentSeemingly, the connection between foreign direct investment and economic development was carefully scrutinised by many countries. Notably, these studies have taken into the consideration many different econometrics methodologies such as regression, ARDL approach , and VECHowever, the advantage of using the first-generation unit root tests assume that cross-section units are cross-sectionally independent .The wavelet coherence approach assists to understand better the bi-dimensional causality of time and frequencies between FDI and economic growth. This approach simply unveils the concealed relationship in cyclical trends and patterns , 87.Dumitrescu and Hurlin Granger causality approach has been optimal in determining the direction of the causal link. It is particularly useful for estimating a model with cross-sectional dependence and heterogeneity. Granger’s causality test performs significantly better when applied to panel data because more observations lead to more degrees of freedom and less collinearity between explanatory variables. Thus, it can be underlined that this analysis can give more handful information with respect to other causality analyses , 89.However, this study employs a combination of methods like panel unit root, wavelet coherence and Granger causality techniques unlike previous research that only used a single method, i.e. panel data analysis.To attain the purpose of the study which was to investigate the direction of causality between FDI and economic growth, the empirical methodology used is presented in multiple stages. Initially the unit root tests were performed to identify the stationary variables, followed by the wavelet coherence technique to observe time frequency dependence of the variables, in subsequence, a panel Granger causality to detect the dynamic relationship between the selected variables: economic growth in terms of GDP per capita and FDI net inflows.The stationarity properties of the variables were determined using the panel unit root tests, which also helped avoid spurious analysis and check if data are not integrated at first order, that is, I(1). According to recent studies, panel-based unit root tests are more powerful than time series-based unit root tests . In ordeThis study further utilised the wavelet approach in solidifying the findings of causality analysis and to observe the time–frequency dependence information between variables, which cannot be profoundly observed through the causality analysis. Dependency of time frequency between FDI, economic growth and other variables were obtained through wavelet approach which was premised on the work of Goupillaud, Grossmann . The usext to yt. The econometric framework considers two covariance stationary variables, x and y, observed for T periods and N individuals. The analytical results of Dumitrescu and Hurlin [αi represents the individual fixed effect across i, and yi,t−k and xi,t−k for the individual i, respectively. The panel is balanced and lag orders p are identical for all cross-section units of the panel. xi,t is said to Granger cause yi,t if past values of xi,t have a significant impact on yi,t in addition to the past of yi,t.Individual Wald statistics proposed by Dumitrescu and Hurlin  are usedd Hurlin  are baseTo test for causality from FDI on economic growth, the Eq  can be sRGDPC is real GDP per capita, ΔFDI is the FDI net inflows, i refers to the country , t refers to the period , p refers to the lag, and εi,t refers to white-noise error terms. This method is vigorous when compared to other causality techniques [Similarly, Eq  is applichniques . In accoMost empirical studies in econometrics aim at analysing the relationship between variables by identifying whether a change in one variable can be predicted by a change in the previous values of another variable. Block Exogeneity Wald test  is perfoOverview of descriptive statistics of the key variables used in the study are presented in The Asian region has the highest standard deviation in net FDI inflows. This is due to the high dispersion of FDI inflows in the region. Asia contains countries with the highest FDI inflow levels such as Hong Kong, and Singapore as well as countries with lower FDI inflows, namely Iraq and Qatar. The lowest standard deviation is in the Mediterranean region. All the countries considered in this region have low levels of FDI inflows, hence, the dispersion and standard deviation are low. Likewise, Europe and Africa have the highest and lowest standard deviations in terms of GDP per capita.Considering GDP per capita from 2010 to 2020, the European continent has recorded the highest value of US$ 118,824 whereas the African continent has the lowest GDP per capita of US$ 234. The maximum percentage of net FDI inflows is captured by the Asian region which is 280%, whilst the European continent has the lowest negative FDI inflows, reflecting disinvestments value of 40%, respectively. The findings also reveal that the minimum net FDI inflows in all regions have negative figures.The trends in the share of FDI in GDP for the countries are shown in The results of the stationarity tests are reported in The Hadri Lagrange Multiplier (LM) test confirms the results from the previous test, with the null hypothesis indicating that the panels are stationary and the alternate hypothesis indicating that some panels contain unit-roots. The results of the Hadri LM test indicate that the p-values of GDP and FDI at the first difference are greater than the significance levels of 1%, 5% and 10%, respectively. Therefore, failing to reject the null hypothesis implies that the panel data is stationary. Thus, it can be derived that both the micro panel variables are integrated at the first order, i.e., I(1) and are stationary at all testing levels.Prior to analysing the findings of interaction effects through Granger causality, the wavelet coherence was deployed to instantaneously detect the correlation and causality between the FDI and other regressors, including economic growth. Interpretation of wavelet coherence requires analysing the area of influence depicted in the grey cone plotted with of R software. The level of significance is depicted by the thick black line determined via the Monte Carlo Simulations and The direction of the arrows will indicate whether the variables move in phase (rightward arrow indicating a positive correlation), or anti-phase (leftward arrow indicating a negative correlation) and the cold (blue) regions of the figure indicate no correlation.In contrast, the warm (red) regions depict the analysed variables are correlated.In 2013 , in the The region of Europe indicates  a ratherConcerning the Mediterranean region  in 2012,The period of 2011 to 2012 reflected a negative correlation between GDP and FDI in the Oceania region , and in For the study, the Granger causality test for heterogeneous non-causality proposed by Dumitrescu and Hurlin  was utilThe bi-directional causality exists between FDI and GDP per capita in the global context at a 1% significance level. Results of the region-wise analysis show bi-directional causality in the Asian region at a 1% significance level, indicating that FDI has substantial predictive power on the economic growth of the Asian countries examined. A uni-directional causality from GDP to FDI exists in the American region at the significance level of 5%. The test findings also indicate no evidence of causality between GDP and FDI in African, European, Mediterranean, or Oceanian regions at 1%, 5%, and 10% levels of significance, respectively, concerning the HENC hypotheses. Moreover, the global analysis and the Asian region confirm the FDI-led growth hypothesis and growth-led FDI hypothesis, while the American region only corroborates the growth-led FDI hypothesis.Tables The results of the The European Sovereign Debt Crisis was considered for Global and European regional analysis. The findings revealed no significant impact from the recession on either GDP per capita or net FDI inflows. The results are reported in the Foreign Direct Investment is often regarded as having a significant impact on economic growth. In other words, FDI is an economic stimulant, particularly in developing, emerging, and impoverished countries. Here, FDI facilitates technology transfer from developed to developing, emerging, and underprivileged countries. It enables domestic investment and institutional improvement and human capital development in the host countries. Similarly, economic growth encourages and supports FDI. The reported bi-directional result for the Asian region is consistent with Liu, Shu  and MahmThe bi-directionality between economic growth and FDI in Asia could be mainly due to foreign investment accelerating economic growth and exposure to new technology, creation of job opportunities, in addition to other reasons. In return, increased economic growth can attract more FDI, resulting in a cyclical relationship between the two variables.The uni-directional causality from GDP to FDI in the American region probably be caused by many of the Latin American developing countries attracting FDI due to economic growth. Another reason is the foreign investors’ view that investments in the Latin American region may produce greater returns in the future.Results obtained for Africa were also substantiated by Mahembe and Odhiambo  for low-The results for the Mediterranean region are consistent with the study by Asheghian , accordiNon-directionality of the variables in Oceania is consistent with the findings of the study by Pandya and Sisombat , in whicGolitsis, Avdiu  and NathThis study intended to assess the causal nexus between FDI and economic growth for 117 selected countries during the 2010–2020 period, using a bivariate panel Granger causality analysis, panel VAR/block exogeneity test and Wavelet Coherence approach, under two classifications; region-wise globally, and region-wise cross-markets as developed, emerging and frontier markets. The research focused on answering one crucial question: does FDI spur economic growth or vice versa?. To measure the dynamic causal relationship between the variables, the study deployed a heterogeneous panel non-causality technique over the other causality techniques. According to empirical findings, the Granger causality analysis for the global context revealed bi-directional causality between FDI and economic growth. The Asian region indicated that if FDI inflows are effectively channelled, economic growth could be improved. In contrast, it was found that a uni-directional causality was present from economic growth to FDI in the American region. The results also confirmed a non-directional causality in the European, Oceanian, Mediterranean, and African regions. Therefore, it can be surmised that FDI inflows contribute to the economy and vice versa. Hence governments should continue to adopt policies that promote a favourable investment climate to attract FDI. The strong tendency of either no Granger-causality or Granger-causality between GDP and FDI suggests that FDI could play a significant role in propelling the economies of these investigated regions. Moreover, the wavelet coherence approach validated the results, enabling the exploration of short-run and long-run causal linkages used to analyse the co-movement between FDI and economic growth.This research identified several policy implications for the host economy to realise the benefits of FDI inflows. The host countries should devise policies that encourage FDI targeting high-growth and priority sectors of the host economy. The host economy should establish these absorptive properties in terms of infrastructure, financial markets, human capital base, market size, and economic and political stability. Identifying these prerequisites and regular review of these in the host country will influence how FDI can reap benefits. Therefore, minimising the potential risks is crucial. In addition, it is advised that the government of both developed and emerging economies should emphasise their attention on encouraging domestic and foreign investment for regional growth.In addition, the host economy should implement reforms to lower barriers, address loopholes in the existing structure and establish a favourable environment that attracts and retains FDI. Sustainability of this conducive environment and revising of policies to adapt to changes in the global environment are also vital.Future studies can expand the analysis by examining more FDI determinants with a sectoral analysis that can reveal the differences across the sectors. Moreover, additional studies can distinguish the causality under various economic conditions (recessions and expansions).S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(XLSX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file.


Prior scholarship demonstrates that older mothers receive more care from daughters, prefer daughters as caregivers, and have stronger emotional bonds with daughters. Despite these clear gendered differences in care, care preferences, and closeness, less is known about whether the presence of daughters in a family affects mother-adult son relationships or whether the presence of sons in a family affects mother-adult daughter relationships. Drawing from theories of gender socialization and social exchange, we propose that mothers would, given the choice between daughters and sons, prefer to receive care from and engage in emotional exchanges with daughters. Therefore, we predict sons’ care to and emotional closeness with older mothers will be inversely related to the number of daughters in the family. We test our hypotheses with mixed-method data from 1,577 mother-adult child dyads nested within 420 families collected as part of the Within-Family Differences Study-II. Findings support our hypotheses. The larger the number of daughters, the less likely sons are to provide care to their mothers, whereas the likelihood of daughters providing care is unaffected by the number of sons. Similarly, the larger the number of daughters, the lower closeness mothers report with their sons, whereas mother-adult daughter closeness is unrelated to the number of sons. In sum, our findings show ways in which both an adult child’s gender and the gender composition of their sibship affect mother-adult child relationships, as well as highlighting the applicability of theories of gender socialization and social exchange to the context of aging families.


Structural coloration takes inspiration from the bright hues found in nature to control the reflection and transmission of light from artificially structured materials. Combining them with active electrical tuning heralds breakthrough applications in optical displays. Compared to pigment- or dye-based approaches, structural coloration generally provides brigher colors with higher color gamut, improved spatial resolution, and resistance to color fading over time. A multitude of photonic concepts and systems have been implemented for this purpose2, ranging from thin film interference, diffraction gratings and photonic crystals3 to plasmonic and dielectric metasurfaces5.Producing vibrant colors has been a driving force for the development of optics, reaching as far back as the multi-colored tableaux found in the windows of medieval churches, or the distinct color-changing appearance of the Lycurgus cup from ancient Roman times. Structural coloration, where micro- and nanostructured materials are used to control the reflection and transmission of visible light at precisely tailored wavelengths, has been a cornerstone of these efforts, taking inspiration from the brilliant hues produced by, e.g., butterfly wings and macaw feathers prevalent in nature6, optical anticounterfeiting7, and colorimetric sensors8. The next crucial challenge for the field is the incorporation of tunability, which can unlock a new generation of planar optical devices for consumer-facing displays and other active optical components. Towards this end, a broad palette of tuning concepts has been examined, such as phase change materials, electrochromic polymers, and stretchable substrates. However, simultaneously achieving bright and tunable structural color while maintaining a dark black state has remained elusive.Building on these advances, many important practical applications of structural coloration have been introduced including high-resolution color printingLight: Science & Applications, T. Badloe and colleagues at the Pohang University of Science and Technology (POSTECH), the Sungkyunkwan University, and the National Institute of Nanomaterials Technology (NINT), Republic of Korea, have demonstrated a tunable all-dielectric metasurface satisfying these requirements, combining an array of elliptical resonators and an electrically controlled liquid crystal cell9. The choice of an anisotropic unit cell geometry for the metasaurface provides a dependence of the optical response on the incident linear polarization, which enables direct light modulation via the liquid crystal cell and therefore a linear transition between bright and dark states of the system  of the lattice. In their analysis, the authors found that a careful tailoring of the geometric metasurface parameters  was key to balance and efficiently couple the different modes in the system.The metasurface platform developed by the authors shows striking performance, with bright red, green, and blue metasurface pixels, a color gamut comparable to the established sRGB standard, as well as high quality white and black states. These capabilities are supplemented by the continuous and fast  modulation between states provided by the liquid crystal cell, taking crucial steps towards displays based on structural color. Such displays hold great promise for use in resource-limited settings where low power consumption is essential. However, to realize the full potential of tunable structural color for such practical applications, important constraints still need to be overcome, including the development of large-area nanofabrication for consumer-scale displays, the extension of the the color range towards wide-gamut standards, and the implementation of increased viewing angles to avoid off-axis color shifts.10. Finally, taking additional cues from nature can deliver a wealth of complementary functionalities for structural color materials ranging from autonomous regulation to self-healing11.These challenges open exciting perspectives for future research on structural coloring, for instance by utilizing machine learning for the inverse design of the nanophotonic geometries


Amyloidoses is a group of diseases characterized by the accumulation of abnormal proteins  in different organs and tissues. For systemic amyloidoses, the disease is related to increased levels and/or abnormal synthesis of certain proteins in the organism due to pathological processes, e.g., monoclonal gammopathy and chronic inflammation in rheumatic arthritis. Treatment of amyloidoses is focused on reducing amyloidogenic protein production and inhibition of its aggregation. Therapeutic approaches critically depend on the type of amyloidosis, which underlines the importance of early differential diagnostics. In fact, the most accurate diagnostics of amyloidosis and its type requires analysis of a biopsy specimen from the disease-affected organ. However, absence of specific symptoms of amyloidosis and the invasive nature of biomaterial sampling causes the late diagnostics of these diseases, which leads to a delayed treatment, and significantly reduces its efficacy and patient survival. The establishment of noninvasive diagnostic methods and discovery of specific amyloidosis markers are essential for disease detection and identification of its type at earlier stages, which enables timely and targeted treatment. This review focuses on current approaches to the diagnostics of amyloidoses, primarily with renal involvement, and research perspectives in order to design new specific tests for early diagnosis. Amyloidoses is a heterogeneous group of diseases, which results from proteins misfolding with the formation of amyloid aggregates accumulated in tissues with subsequent progressive organ dysfunction and failure ,2. AmyloThe triggers of amyloidogenesis are not yet fully discovered. In the case of localized amyloidoses, individual organs may be affected by local production of amyloid protein in skin, soft tissues, urinary bladder, digestive tract, respiratory tract, and others . The circulation of amyloidogenic proteins in systemic disease leads to amyloid deposition in multiple tissues throughout the body  Figure . SystemiIn the context of pathological processes, several diseases of the central nervous system (CNS), such as Alzheimer’s diseases and Parkinson’s diseases, form a specific distinct category in the amyloidosis entity. These disorders could result from the toxic effect of soluble oligomeric amyloid aggregates, rather than structural tissue alterations due to amyloid deposits, as it shown in cell culture and animal models ,24. CellThe diagnosis of the amyloidosis type is critical for assigning therapies, reducing the specific protein level in the body, and inhibiting the pathological processes associated with this protein ,27. The 99mTc-labeled bone scintigraphy tracers and their accumulation in the myocardial amyloid deposits. This imaging technique, in fact, has been designed exclusively for the detection of cardiac ATTR amyloidosis in the absence of plasma cell dyscrasia [Currently, there are different approaches based on immunodetection and mass spectrometric technologies that enable the type of amyloidosis to be determined by analysis of Congo red positive biopsy specimen . Currenyscrasia . Radioacyscrasia . This meyscrasia . Hence, There have been previously published reviews considering methods of early noninvasive diagnosis of CNS amyloidosis and their significance for the effective monitoring and management of the disease ,38,39. TIn systemic amyloidoses, kidney involvement is known to be very frequent and usually manifests with nephrotic syndrome and chronic kidney disease . NowadayAL-amyloidosis is the most common type of systemic amyloidosis in developed countries  and mainFGA gene [AA-amyloidosis is another common type of renal amyloidosis , charactFGA gene . AmyloidEarly diagnostics of systemic amyloidosis is crucial as the disease has unfavorable prognosis if left untreated . The medThe therapeutic efficacy is critically dependent on the stage of disease. The high mortality in AL amyloidosis  to a greIn order to assess the degree of organs involvement and to clarify the type of amyloidosis, a number of noninvasive imaging tools could be used, such as echocardiography, magnetic resonance imaging, and imaging of radioactive tags injected into the circulation ,76. SAP Suspected diagnosis of systemic amyloidosis with renal involvement should be proven by a morphological analysis of a kidney specimen. Alternatively, in a case of contraindications for kidney biopsy, one may consider an analysis of extrarenal tissue such as bone marrow, liver, and abdominal fat . HoweveKidney biopsy specimens are studied using light microscopy, immunoassays, and electron microscopy. Special Congo red staining shows detected amyloid material as a red color under light microscopy and as apple green birefringence under polarized light as a result of dye binding with amyloids ,33. ImmuThe most effective approach for diagnosing amyloidosis and its type is laser microdissection followed by tandem mass spectrometry (LMD–MS) of biopsy tissue specimens . ProteinTTR gene including Val30Met, Val122Ile, Thr60Ala, and AFib amyloidosis is caused by point mutations  or frameshift mutations in the FGA gene [MEFV, NLRP3, MVK, and other genes [http://amyloidosismutations.com/ (accessed on 19 September 2022) [Mutation studies for various hereditary amyloidosis are performed to verify the amyloidosis type identified by biopsy analysis and also to refine the disease predicting . SpecifiFGA gene ,96. Whener genes . A curreer 2022) . Geneticer 2022) . Notablyer 2022) ,100. A mer 2022) .Thus, the analysis of biopsy-derived material is an effective method of diagnosing the amyloidosis type. However, kidney biopsy is generally performed by indication in the case of pronounced organ dysfunctions and higher risks of treatment failure. Another major disadvantage of this approach is the invasive nature of the procedure and risk of complications that limit its use in certain cases.123I-labeled SAP scintigraphy provides detection of either AA- or AL- amyloidosis types with 90% sensitivity. However, this approach has limited value because of overlapping patterns of organ involvement for both types of amyloidosis [99mTc-labeled bone scintigraphy tracers into circulation followed by the visualization of their accumulation in myocardial amyloid deposits provides specificity and a positive predictive value of 100% for the diagnosis of ATTR cardiac amyloidosis, but only in the absence of plasma cell dyscrasia [A major area of noninvasive diagnostics is the development of scanning research methods . Currently, the application of those methods is limited to the late stages of amyloidosis in the presence of the significant deposition of amyloid aggregates in the organs ,103,104.loidosis . Injectiyscrasia . At the yscrasia . Positroyscrasia ,107 enabyscrasia . Researcyscrasia . HoweverAnother area of noninvasive diagnosis is the analysis of body fluids , which are collected without damaging the internal organs affected by amyloidosis. This approach provides opportunities for detecting factors and disease markers before the occurrence of severe systemic abnormalities that are recalcitrant to therapy. Fluid analysis, firstly, simplifies the condition monitoring of patients with already diagnosed amyloidosis and, secondly, enables the screening of the early stages of disease until progressive systemic abnormalities become apparent.Since the 1970s, there have been several attempts to detect amyloid aggregates in the urine. Several studies have demonstrated the presence of different types of fibrillar structures in the urine in amyloidosis ,110. ThiNowadays, there are a variety of methods for detecting the precursor protein of amyloidosis in serum and urine. Palladini et al. demonstrated that immunofixation electrophoresis of serum and urine (IFE) performed with anti-IgG, -IgA, -IgM, -Igκ, and -Igλ antibodies on gels could identify the amyloidogenic Ig light chains in all 115 patients with a monoclonal gammopathy . The serThe possibility of detection of precursor proteins in biological fluids by MS is currently being studied , despitCaenorhabditis elegans as an object for testing the toxicity of a monoclonal protein (“biosensor”) has demonstrated the possibility of diagnosing the cardiac AL amyloidosis in MM patients by the level of pathogenic effects on the pharynx of nematode [LV6-57, LV3-01, and LV3-21 are associated with renal injury, LV1-44 is more frequently identified in patients with cardiac AL amyloidosis, LV2-14 and KV1-33 usage are more probable if peripheral nerve and liver, respectively, are involved [New perspectives in the analysis of precursor proteins of AL amyloidosis include the assessment of the Ig light chain functional properties detected in body fluids. The glycosylation of precursor proteins, their toxicity, and the genes encoding the monoclonal protein provide a high-level confidence in predicting of amyloidosis in a group of patients with MGUS, smoldering myeloma, or MM ,130,131.nematode . Kumar enematode . Kumar einvolved . These aThus, the available range of noninvasive methods in the amyloidosis evaluation seems to be useful in clarifying the organ involvement, assessment prognosis, and disease monitoring . HoweverIn the absence of noninvasive methods of early diagnosis for the majority of amyloidosis, it is necessary to carry out research with new approaches. One of the trends is to use specific properties of amyloid aggregates and precursor proteins. These properties include the seeding of amyloidogenic protein monomers by preexisting aggregates , amyloidAmyloid aggregates, characterized by the presence of an array of β-strands, are known to induce and promote the formation of new aggregates by monomers of these proteins . The adIGKV 1–33 germline gene 91–96%) varies significantly in various combinations [IGKV 1-33 48%) [One of the challenges in applying the protein amplification approach to AL amyloidosis is the unique nature of each Ig light chain due to the complementarity-determining regions of the variant domain. This problem could be solved by selection of the monomeric protein required to be induced by the aggregates from the biological fluids. The amino acid sequence of the selected protein will differ from the sequence of Ig light chains and their fragments in aggregates obtained from different patients. Therefore, the amplification reaction must proceed through cross-seeding between heterologous proteins . Blancasinations . Cross-sinations . The aut-33 48%) .IGKV 1-33 product can accelerate fibril formation in a solution of full-length Igκ monomers. That result raises the issue of considering the use of Igκ constant domain monomers for the detection of amyloidogenic monoclonal proteins in biological fluids. Since the constant domain is unchanged in all Igκ variants except for rare mutations, its use can provide a stable seeding with lower effects on aggregation kinetics varying between samples. It was demonstrated that monomers of the constant domain of Igκ light chains exhibit in vitro self-aggregation with the forming of amyloid fibrils [Another interesting finding of  was the  fibrils . In addi fibrils . The suc fibrils . Amyloid fibrils . A different approach for the optimization of monoclonal protein amyloidogenicity assessments is the development of universal standard aggregates of Ig light chains. For the testing amyloidogenicity of Ig light chains,  used synThe assessment of amyloidogenicity of protein components and detection of amyloid aggregates in biological fluids are complicated by the presence of a large number of other proteins (not participating in amyloidogenesis). Specifically, albumin, the most abundant protein in serum and in urine samples from patients with nephrotic syndrome can inhibit amyloid formation . Martin g and treatment of the deposit with ionic detergents, such as sarcosyl and sodium dodecyl sulfate. It provides detergent-resistant aggregates from the sample and can be used for research and diagnostic purposes [Alternatively, one way to dispose of bulk protein and prepare a sample to assess the amyloidogenicity of the protein components is ultracentrifugation at speeds in the range of thousands purposes . Ultracepurposes . Accordig enables the removal of large fibrils, the presence of which is not necessarily associated with amyloidogenic factors in the sample and can be found in healthy humans [Generally, the obtained aggregates contain practically no albumin, and preliminary centrifugation at a speed of 4000× y humans . The anay humans ,156; seey humans ). Of inty humans ,158. They humans . PerformThe current arsenal of diagnostic approaches for renal amyloidosis is based primarily on invasive procedures applying typically at late stages. Since the effectiveness of renal amyloidoses treatment largely depends on the stage at which the disease is diagnosed the design of noninvasive screening techniques for renal amyloidosis might enable earlier detection of the disease, and significantly improve the renal and life prognosis in these patients. In this regard, further study of functional and pathological amyloid properties in humans is essential for the development of new diagnostic and treatment methods for amyloidosis.


Many gut microbiota metabolites, such as fatty acids, amino acids, and bile acids, convey signaling functions as they mediate the crosstalk between gut microbiota and host physiology. Amino acids' abundance and species alteration, including glutamate and tryptophan, may disturb the signaling transmission between nerve cells and disrupt the normal basal ganglia function in PD. Specific amino acids and their receptors are considered new potential targets for ameliorating PD. The present study aimed to systematically summarize all available evidence on the gut microbiota-derived amino acid metabolism alterations associated with PD.Non-motor symptoms (NMS) of Parkinson's disease (PD), such as constipation, sleep disorders, and olfactory deficits, may emerge up to 20 years earlier than motor symptoms. A series of evidence indicates that the pathology of PD may occur from the gastrointestinal tract to the brain. Numerous studies support that the gut microbiota communicates with the brain through the immune system, special amino acid metabolism, and the nervous system in PD. Recently, there is growing recognition that the gut microbiota plays a vital role in the modulation of multiple neurochemical pathways  Parkinson's disease (PD) is the second most common neurodegenerative disease and affects an estimated 3 million people worldwide. The typical feature of PD is the accumulation of intracellular aggregates called Lewy bodies, composed largely of the presynaptic protein alpha-synuclein , constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and small intestinal bacterial overgrowth syndrome (SIBO), were associated with PD by affecting the central nervous system  symptoms. Specifically, the association between intestinal disorders and PD pathogenesis attracting many researchers' attention may be due to the existence of the gut-brain axis. Overall, the PD risk was higher in IBS patients than others, indicating that the intestinal disorder may serve as a warning sign for PD. Further research is warranted to explore the underlying mechanisms of this correlation.The key pathological characteristics of PD are the accumulation of α-syn and cell death in the brain's basal ganglia, affecting an estimated three million people (more than 60 years of age)  is mainly characterized by medium-sized hydrophilic molecules transporting along their concentration gradient in a system without the assistance of a carrier system   , and butyrate   constitute a major class of fermentation products. The microbiota-derived carbohydrates of SCFAs are cardinal examples of beneficial metabolites  transporters, which contain a large number of families of distinct transporters, are adopted to transport amino acids and peptides (including di- and tripeptides). Many above-mentioned transporters are expressed in the large intestine. There is evidence for transporter expression at different levels, such as the protein level and the gene expression level. Peptide transporter 1 (PEPT1), encoded by SLC family 15 member 1 (SLC15A1), is involved in the intestinal uptake of oligopeptides and peptide-mimetic drugs , which are involved in the degeneration of the nigrostriatal system based on the excitotoxicity mechanisms. All the studies have shown that GMBA may be significantly correlated with PD pathogenesis.Although microbiota-host interaction has drawn much attention both from clinicians and researchers in recent years, it still calls for a deeper understanding of the complex GMBA communication. Furthermore, microbiota-derived amino acid metabolism is a crucial factor suggesting major perturbations of the microbiome. These studies illustrated that amino acids metabolized by gut microbiota might affect the degeneration of the nigrostriatal system in PD patients. Gut microbiota and amino acids may be potential therapeutic targets for PD.GZ and YZ contributed to the conceptualization. WW and GZ contributed to the investigation and funding. WW, GZ, SJ, CX, YL, and LT contributed to the writing and final approval. All authors contributed to the article and approved the submitted version.This work was funded by the National Natural Science Foundation of China (82204375 and 82003933), the Science and Technology Development Planning Project of Traditional Chinese Medicine of Jiangsu Province of China (QN202103), the Natural Science Foundation of Nanjing University of Chinese Medicine (XZR2021046), the Nanjing Medical Science and Technology Development Project (YKK20167), and Nanjing Youth Talent Training Plan of TCM (ZYQ20006).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Spinal cord injury (SCI) is a devastating central nervous system disease caused by accidental events, resulting in loss of sensory and motor function. Considering the multiple effects of primary and secondary injuries after spinal cord injury, including oxidative stress, tissue apoptosis, inflammatory response, and neuronal autophagy, it is crucial to understand the underlying pathophysiological mechanisms, local microenvironment changes, and neural tissue functional recovery for preparing novel treatment strategies. Treatment based on cell transplantation has become the forefront of spinal cord injury therapy. The transplanted cells provide physical and nutritional support for the damaged tissue. At the same time, the implantation of biomaterials with specific biological functions at the site of the SCI has also been proved to improve the local inhibitory microenvironment and promote axonal regeneration, etc. The combined transplantation of cells and functional biomaterials for SCI treatment can result in greater neuroprotective and regenerative effects by regulating cell differentiation, enhancing cell survival, and providing physical and directional support for axon regeneration and neural circuit remodeling. This article reviews the pathophysiology of the spinal cord, changes in the microenvironment after injury, and the mechanisms and strategies for spinal cord regeneration and repair. The article will focus on summarizing and discussing the latest intervention models based on cell and functional biomaterial transplantation and the latest progress in combinational therapies in SCI repair. Finally, we propose the future prospects and challenges of current treatment regimens for SCI repair, to provide references for scientists and clinicians to seek better SCI repair strategies in the future. Spinal cord injury (SCI) is a complex and challenging destructive disease of the central nervous system, resulting in permanent motor and sensory dysfunction due to disruption of neural circuits composed of descending motor neurons and ascending sensory neurons. In addition, because SCI is a serious injury caused by multiple primary and secondary mechanisms simultaneously or sequentially, it often results in chronic consequences such as respiratory dysfunction, cardiovascular complications, neuropathic pain, spasticity, bladder and bowel dysfunction, and mental illness , 2. The The spinal cord originates from the end of the neural tube during the embryonic period, and the lumen of the primitive neural tube forms the central canal of the spinal cord. The spinal cord in the lower part of the central nervous system retains segmental structure and connects with 31 pairs of spinal nerves distributed in the trunk and extremities. The spinal cord is located in the spinal canal and is surrounded by 3 layers of membranes , which are consistent with the curvature of the spine. The spine itself consists of cervical, thoracic, lumbar, and caudal segments . The uppThe function of the spinal cord is as follows. First, it receives somatic and visceral sensory information in most areas of the body, and this information is relayed in the spinal cord for preliminary integration and analysis. Part of the relayed information is transmitted upward to the higher center, and part is transmitted to motor neurons and other spinal cord neurons. Second, an ascending conduction pathway is sent to upload the relayed sensory information and the information of the spinal cord itself to the higher center. Third, it sends out motor fibers, manages body movement and visceral activity, and is the lower center of body and visceral movement. Fourth is the center of various basic reflexes. Last, through the descending conduction pathway, it relays the information transmitted by the superior center, accepts the control and regulation of the superior center, and completes the functions of the superior center.The pathological process of SCI includes primary and secondary injuries  Figure . The forSecondary injuries are usually divided into the following stages: acute phase (<48 h), subacute phase (48 h-14 days), intermediate phase 14 days-3 months), and chronic phase (>3 months) , 21. The months, According to the location and degree of spinal cord injury and clinical manifestations, we often divide it into different syndromes. These include central cord syndrome, anterior cord syndrome, conus medullaris syndrome, cauda equina syndrome, and Brown-Sequard syndrome. The central spinal cord syndrome mostly occurs in the injured area of the cervical spine, and the conus medullaris syndrome and the cauda equina syndrome are mostly related to the injury of the conus medullaris and lumbosacral nerve roots. Anterior cord syndrome and Brown-Sequard syndrome are often accompanied by varying degrees of motor function loss and changes in pain and temperature sensation.After SCI, changes in the local microenvironment can cause dynamic changes in resident cells such as neurons, astrocytes, oligodendrocytes, and microglia, including cell phenotype, number, and distribution. Understanding the dynamic changes of cell behavior could help develop better strategies for neural regeneration.The neurons of the spinal cord are divided into different categories, including motor neurons, sensory neurons, excitatory neurons, inhibitory neurons, and relay neurons of the spinal cord itself. After SCI, the damage and apoptosis time and degree of damage of various types of neurons are different. In the transection injury model, neurons undergo apoptosis 1 hour after injury and are localized to the injury site . In the Astrocytes are the most abundant cells in the nervous system. They can provide a variety of neurotrophic factors and energy substances, regulate the metabolism of glutamate and potassium ions and the water content in the spinal cord, and participate in various physiological behaviors of neurons. They also play a role in the resistance to oxidative stress and excitotoxicity , 36. NaiOligodendrocytes are involved in the formation of myelin, and primary injury of the spinal cord and secondary excitotoxicity and reactive oxygen species can have a serious impact on them. Damage to oligodendrocytes and myelin inhibits the propagation of action potentials, decreases effective conduction of nerve signals, and will lead to functional impairment . StudiesMicroglia are immune cells with self-renewal ability and are an important part of the immune function of the central nervous system , 44. AftFollowing SCI, early massive cell death and degeneration of spinal cord structure lead to a loss of parenchymal tissue in the central area of the injury, forming cystic cavities with extracellular fluid, connective tissue bands, and infiltrating macrophages , 48. TheThe immune cells of the central nervous system mainly include microglia and macrophages around blood vessels, meninges, choroid plexus, and periventricular. Microglia, as resident cells of the central nervous system, are rapidly activated after SCI, transform into phagocytic microglia, and migrate and aggregate to the site of injury at the same time , 52. A sAfter SCI, astrocytes, the most abundant resident cells in the central nervous system, begin to proliferate and transform into reactive astrocytes, which interweave to isolate the injured area from the normal area . Over tiChondroitin sulfate glycoproteins are widely expressed in the central nervous system and are closely associated with cell migration and axonal growth , 67. CSPSCI leads to oligodendrocyte death and myelin damage, which affects nerve signaling. At the same time, myelin-related components such as myelin-associated protein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) are also the inhibited factors of axonal growth . In addiAfter SCI, the final repair effect is often unsatisfactory due to its limited ability of nerve regeneration. The injury-induced syringomyelia, glial scarring, inflammatory responses, and the local inhibitory microenvironment caused by release and accumulation of axonal growth-inhibiting substances also play an important role. At present, the recognized nerve repair mechanism of SCI includes two aspects. On the one hand, the intrinsic motor nerves of the spinal cord regenerate through their axons, cross the area of injury, establish connections with distant neurons, and remodel neural circuits . Some scThe current treatments after SCI include maintaining the stability of the spinal cord after injury, early surgical decompression, and corresponding treatment measures from the aspects of neuroprotection and nerve regeneration. The goal of postinjury spinal cord fixation is to avoid additional trauma, while early surgical decompression relieves persistent compression and avoids further expansion of ischemia and nerve tissue damage , 85, 86.Neuroprotective strategies include drug therapy such as glucocorticoid methylprednisolone, sodium channel blocker riluzole, and nondrug therapy such as cerebrospinal fluid drainage, blood pressure augmentation, and therapeutic hypothermia. Methylprednisolone can enhance neuron survival after injury by regulating the release of anti-inflammatory cytokines and attenuating oxidative stress, and riluzole reduces excitotoxicity influence to cells by preventing sodium influx and regulating glutamine release. Combined treatment of cerebrospinal fluid drainage and blood pressure augmentation can increase the blood supply and perfusion pressure in the injured area and prevent ischemic injury. Therapeutic hypothermia can reduce the basal metabolic rate of the central nervous system and improve the inflammatory response at the site of injury, while also reducing oxidative stress and excitotoxicity , 87–90.In recent years, research in the field of nerve regeneration has gradually become a hot spot in the field of SCI repair, especially treatment strategies based on cell transplantation and functional biomaterials, which have given people better expectations for the prognosis of SCI patients. In addition, treatment regimens for Rho-ROCK inhibitors and anti-NOGO antibodies have also shown certain therapeutic effects in animal models and clinical trials , 92.Cell-based regenerative therapy is a very promising direction for the treatment of SCI, including both exogenous cell transplantation and enhancement of endogenous stem cell function –95. We c(1) Neural Stem Cells. Neural stem cells are self-renewing cells with multiple differentiation potentials that can differentiate into neurons, astrocytes, and oligodendrocytes under different conditions [nditions , 103. Thnditions , 105. Acnditions , 107. Sc(2) Mesenchymal Stem Cells. Mesenchymal stem cells are self-renewing cells with multiple differentiation potentials [tentials . It can tentials –112. Stutentials , 114. Sitentials . Reviewitentials –121. In tentials , 122–124tentials .(3) Induced Pluripotent Stem Cells. Induced pluripotent stem cells are cells with self-renewal and multidifferentiation potential, which are generated by genetic modification and reprogramming of differentiated somatic cells, avoiding ethical and immune rejection, and bringing more possibilities to regenerative medicine [medicine –129. Stumedicine , 131. Anmedicine .(4) Astrocytes. Naive astrocytes are activated after SCI to form reactive astrocytes that prevent the expansion of injury and inflammatory responses, and the formation of astrocyte scars is often thought to inhibit axon regeneration [neration , 65, 133neration , 135. Afneration . How to (5) Oligodendrocyte Precursor Cells. Oligodendrocyte precursor cells can be rapidly activated after SCI, proliferate massively, and differentiate into oligodendrocytes and Schwann cells to promote remyelination [lination . Animal lination , 139. Fu(6) Olfactory Ensheathing Cells. Olfactory ensheathing cells are specialized types of glial cells present in the peripheral and central nervous systems and are found in the olfactory mucosa and olfactory bulb [ory bulb , 141. Itory bulb –144. Somory bulb , 145. Itory bulb . At pres(7) Schwann Cells. Schwann cells are the most numerous glial cells in the peripheral nervous system and are an important part of nerve regeneration in the peripheral nervous system [s system . In anims system –152. In s system .(8) Genetically Modified Cells. With the development of gene technology and cell culture technology, scholars are also trying to use gene-modified cells to treat SCI. It can more efficiently express the required protective nerve growth factor, enhance the differentiation of neural stem cells or progenitor cells into neurons, and improve the survival rate of transplanted cells, thereby improving the effect of cell therapy and promoting the regeneration and repair of SCI [r of SCI –156. Accr of SCI , 158. Sor of SCI . There ar of SCI . In the With the increasing number of attempts to treat SCI with cell transplantation, some problems have also been identified, for example, the survival rate of transplanted cells is low, the extravasation of transplanted cells at the injury site, and how to make the transplanted cells function better at the injury site. Researchers have also made many attempts in this regard. Intrathecal injection of neurotrophic factors , growth factors , etc. has been reported to enhance the survival of transplanted cells . Using gAnother direction of cell therapy is to fully exploit the regenerative potential of endogenous stem cells . FollowiAfter SCI, the huge gap formed by the loss of neural tissue is the main obstacle to axon regeneration and neural circuit repair. At the same time, the therapeutic effect of simple cell therapy is limited by local severe inflammatory response, extravasation of transplanted cells, and poor cell survival rate. In order to achieve a more ideal therapeutic effect, people try to transplant and integrate biomaterials into the injured spinal cord tissue. Initially, people only tried to find suitable biomaterials, which, through certain processing, were structurally suitable for implantation into the injured area and acted as a “bridge” to support and guide axon regeneration . With thEssential elements of functional biomaterials include good biocompatibility, suitable biodegradability, and low immunogenicity , 184. MoWe divide functional biomaterials into the following four categories according to their main components and preparation methods: natural materials, synthetic materials, composite materials, and micro-/nanomaterials –191. Natα was combined with chondroitinase. The functional bioactive scaffolds can maintain ChABC activity with long-term slow release and enhance the recruitment of endogenous neural precursor cells, ultimately promoting tissue regeneration [After SCI, due to the complex and dynamic changes in the pathophysiological mechanisms affecting nerve repair, people have developed and prepared a variety of functional biomaterials based on injury factors and nerve repair mechanisms, which have shown gratifying effects in animal models. Clinical trials have been carried out. From the perspective of promoting axonal growth and reformation of neural circuits, some scholars have combined PLGA microspheres loaded with FGF2 with a biopolymer mixture hydrogel containing hyaluronic acid and methylcellulose, which can repair SCI through local delivery and sustained release effects . Some scneration –219. Somneration . Consideneration , 222. Naneration , 188. Fineration . Furtherneration . It has neration –227. Nanneration . Li et aneration .SCI leads to disruption of neural circuits, tissue loss, and cyst formation. Both cell transplantation and functional biomaterial transplantation have been proven to effectively promote the repair of nerve tissue after SCI. In order to improve the therapeutic effect and repair efficiency, people have tried to combine cells with functional biomaterials to treat SCI.The methods of combining cells and functional biomaterials to treat SCI mainly include the following: the first mixes cells with functional biomaterials in vitro to form a tissue-like matrix, which is then implanted at the injury site. The second is the simultaneous injection of self-assembled biomaterials and cells into the injury site to form tissue scaffolds containing cells in vivo. The first two are mostly used for gel materials. The third type is to plant cells on the prepared bioactive scaffolds in vitro and then implant the scaffolds with cells into the damaged area. Most of the scaffolds have a fixed shape. The fourth type is to implant prefabricated scaffolds into the injury and then inject cells around the material to promote the integration of the biomaterial with the injured tissue. The latter two categories are mostly used for solid-state biomaterials .Functional biomaterials can not only fill the lesion cavity and provide physical support for axonal regeneration, but their unique biological functions can also effectively promote axonal growth and angiogenesis, regulate immune responses, alleviate scar inhibition, and help transplant cell survival and differentiation. Transplanted cells can secrete trophic factors necessary for nerve repair and promote axon regeneration and endogenous stem cell migration, and neural stem/progenitor cells can also differentiate into relay neurons to integrate damaged neural circuits. In addition, biomolecules released from functional biomaterials and transplanted cells can also downregulate the concentration of growth inhibitory components  caused by nerve injury and improve the local microenvironment . It has The regeneration and repair process of SCI is complex and affected by many factors, and its pathophysiological mechanism still needs further research by scholars. In recent years, many preclinical studies have been carried out based on cell transplantation, functional biomaterials, and their combination therapy, and some studies have been carried out to the clinical trial stage. Although evidence shows that most of the research is beneficial to the repair of SCI and the improvement of motor function, there are still many problems before it can be used in clinical practice and for the benefit of patients. Different types of SCI, patient conditions including age and underlying diseases, severity of injury, and different lesion volumes are suitable for different treatment modalities. When using cell transplantation to treat SCI, the selection of cell types, the number of cells to be transplanted, and the exact location and method of transplantation will affect the therapeutic effect. Inappropriate treatment may result in poor cellular viability, poor cell differentiation, and tumor formation, all of which need to be further addressed and standardized. In addition, due to the complexity of organisms, the biological functions of some cells have two sides, and it is necessary to explore the balance point of treatment. For example, naive astrocytes are activated after SCI to form reactive astrocytes, which prevent the expansion of the injury and inflammatory response, and their eventual formation of astrocyte scars is often considered to inhibit the regeneration of axon. However, some scholars inhibited the growth of reactive astrocytes by gene editing but did not help tissue regeneration. On the contrary, studies showed that the regeneration ability of axons was reduced. Oligodendrocyte precursor cells can differentiate into oligodendrocytes and Schwann cells, which act as substrates for remyelination, regulate local immune function, and secrete a variety of trophic factors, cytokines, chemokines, etc. They aid in myelination and tissue repair. However, they can also hinder axonal regeneration by promoting CSPG deposition to form inhibitory glial scars. Researchers need to use a variety of research methods such as omics sequencing to reveal the dynamic changes and interactions of cells in the process of growth and differentiation, so as to achieve better therapeutic effects. When using functional biomaterials to treat SCI, the key point is whether the tissue structure and biological function can be simulated to the greatest extent, whether the functional biomaterials can release biomolecules continuously and provide nerve cells, axonal structures, and extracellular matrix similar to natural tissues at the same time, and whether it can repair injury through specific therapeutic targets while having the degradation properties and degradation products that match the tissue recovery. Combining functional biomaterials with cell transplantation for the treatment of SCI is a promising treatment modality. This combined strategy provides the transplanted cells with a physical matrix for adhesion, proliferation, and differentiation and improves the survival rate of cell transplantation. Functional biomaterials play a regulatory role through specific therapeutic targets and are more conducive to the formation and continuous growth of new axons, forming tissue bridges, integrating the materials into the host, and finally forming a complete neural circuit. In addition to the treatment modalities highlighted in this article, other single or combined strategies  have also been used to treat SCI. Considering the complexity and diversity of the pathophysiological mechanisms of SCI, combined strategies often show better therapeutic effect. In addition, technologies such as allogeneic spinal cord tissue transplantation, spinal cord organoid research, and bioengineered spinal cord-like tissue construction have also been tried to be applied to the treatment of SCI . How to In this paper, we started from the anatomical structure of the spinal cord, the pathophysiological changes after injury, and the regeneration and repair mechanism of spinal cord nerves, and then, we discussed treatment methods based on functional biomaterials and cell transplantation. All in all, considering the complex pathophysiological mechanisms and dynamic changes of SCI, the combined therapy of the two has great potential for clinical translation in the future and is expected to provide new hope for patients suffering from SCI. Of course, the combination therapy strategy also requires the cooperation of scholars from different disciplines such as medicine, chemistry, biology, and tissue engineering to provide more effective and safer treatment options for SCI.


Articular cartilage has limited self-regeneration ability for lacking of blood vessels, nerves, and lymph that makes it a great challenge to repair defects of the tissue and restore motor functions of the injured or aging population. Platelet derivatives, such as platelet-rich plasma, have been proved effective, safe, and economical in musculoskeletal diseases for their autologous origin and rich in growth factors. The combination of platelet derivatives with biomaterials provides both mechanical support and localized sustained release of bioactive molecules in cartilage tissue engineering and low-cost efficient approaches of potential treatment. In this review, we first provide an overview of platelet derivatives and their application in clinical and experimental therapies, and then we further discuss the techniques of the addition of platelet derivatives and their influences on scaffold properties. Advances in cartilage tissue engineering with platelet derivatives as signal factors and structural components are also introduced before prospects and concerns in this research field. In short, platelet derivatives have broad application prospects as an economical and effective enhancement for tissue engineering–based articular cartilage repair. Articular cartilage is a highly specialized connective tissue whose function is to provide a smooth, lubricated surface for articulation. As simple tissue without blood vessels, nerves, or lymphatics, it is nourished with oxygen and nutrients diffused from the synovium and the subchondral bone. The total volume of cells in human articular cartilage is only 1.65% on average , and thevia trauma, abnormal wear of an instable joint, excessive load such as sports injuries or obesity, or simply during the aging process. The aforementioned are the main causes of osteoarthritis (OA) and the rapid increase in the incidence of OA, primarily driven by the aging global population, leads to an annually increasing burden on health services and societies worldwide , an autologous blood product containing growth factors (GFs), and cytokines have gained significant interest owing to the safety of its autologous origin and relative ease of production. Numerous studies support that PRP has beneficial effects on cartilage pathology and alleviation of pain . It is aTo overcome the limitations of surgical treatments, such as injury or insufficient supply of the donor site and the potential risk of viral transmission in allograft transplantation, cartilage tissue engineering (CTE) has gained a lot of attention and achievements over years . Tissue Suitable cells for hyaline cartilage construction include autologous chondrocytes and mesenchymal stem cells (MSCs) obtained from different tissues such as bone marrow, adipose tissue, umbilical cord, synovial membrane or synovial fluid, and chondrogenic progenitor cells (CPCs) . AlthougThe signal factors used in CTE are supposed to mediate growth, proliferation, and differentiation of seeded cells by specific pathway activation and stimulate synthesis and secretion of relevant proteins and glycoproteins for ECM generation and maintenance. Transforming growth factor-β (TGF-β), bone morphogenetic proteins (BMPs), insulin GFs, and fibroblast GFs are among the most popular GFs in cartilage formation . HoweverIn this review, the characteristics of platelet derivatives and biomaterials, their interaction, and the technology of their combination are discussed. Challenges associated with the use of platelet derivatives in cartilage defects and recommendations for future directions are considered in the final section.Platelets are cytoplasmic fragments of multinucleated megakaryocytes with a life span of 7–10 days, and they play an important role in hemostasis and other aspects. Secretory granules, including ɑ-granules, dense granules, and lysosomes, are critical for normal platelet functions . Among tPRP refers to a sample of plasma with platelet concentrations above baseline values. One million/ml of platelet count is required based on the working definition, which is approximately five times that of whole blood, based on studies of cell proliferation and tissue healing . It is oIn vitro studies suggest that leukocyte-rich PRP had higher levels of GFs and interleukin-1 receptor antagonist than leukocyte-poor PRP  is prepared by PRP with two or three freeze–thaw cycles in order to break the platelet membranes and release the bioactive molecules, and the remnants are removed by centrifugation as illustrated in Platelet-derived extracellular vesicles including exosomes and microvesicles are regarded as important effectors of platelet derivatives for encapsulation of bioactive content and enrichment of micro RNAs . Their iRegarding the acting mechanism of platelet derivatives, the most current researches on their promotion of cartilage regeneration stayed at the level of therapeutic effect, and the mechanisms behind are rarely studied because of their complex composition. We believe that the in-depth mechanism research will effectively promote the progress of platelet derivatives in CTE.Activation of platelet concentrates leads to not only the release or derivation of stored GFs and cytokines but also rapid translation of preexisting mRNA . Typicalvia connection to integrin receptors on collagen or gelatin that initiate the degranulation and the release of GFs without additions or mechanical forces , and GF content , and thePlatelet derivatives have been applied in fields including wound healing, dental and oral surgery, and sports medicine . There aPRP has been reported to significantly downgrade the expression of inflammation-induced cytokines and chemokines in chondrocytes, thus preserving proliferation and chondrogenic phenotypes reduced by pro-inflammatory cytokines with or without the enhancement by hyaluronic acid (HA) . AlthougIn cartilage repair, platelet derivatives increase chondrocyte viability, proliferation, and migration . Chondroin vitro expansion of human bone marrow mesenchymal stem cells (BMSCs) for tissue-engineering applications based on findings that BMSCs cultured in media with PL and deprived of serum showed a high proliferation potential and formed organized ECM with embedded chondrocytes in lacunae  hydrogel, with the increase in PRP concentration, the compressive strength and elastic modulus increase, while the degradation is accelerated. In addition, the addition of PRP decreases the gelation rate and forms a more homogeneous structure . Similarus value . In concin vitro, decellularized with chemicals or devitalized by physical methods to minimize their immunogenicity  and keratan sulfate are the main GAGs in adult articular cartilage . In part network . Both HA network . Santo e network .SF is a protein-based polymer derived from silk produced by insects such as silkworms and spiders. It is immunologically inert and possesses low inflammatory potential, purified by complete removal of potential inflammation-inducing proteins and debris . The degCompared to some proteins, polysaccharides do not suffer from some of the disadvantages, such as immunogenicity and potential risk of animal-originated pathogen transmission. Chitosan is a natural polysaccharide derived from chitin, a structural element in the exoskeleton of crustacean, which is easily extracted from the protective shells of crabs and shrimp . It is din vitro cultivation  acids are the most widely used synthetic degradable polymers such as polycaprolactone, poly (glycolic acid), poly (lactic acid), and their copolymers . BioresoInorganic materials, including metallic materials, bioactive glasses, and bio-ceramics, are widely used in bone tissue engineering, for their load-bearing ability . As one in vitro model for study of integration , beta-tricalcium phosphate (β-TCP), and their mixture known as biphasic calcium phosphate. In addition structure-based osteoconductivity, they also serve as a source of calcium ions for ossification through surface dissolution . They haegration . Soakingegration . Jang etegration .in vivo. In particular, the BMP-2 expression is significantly increased with the treatment of PRP, which indicates platelet derivatives as stimulators of transferred genes (Combination of inorganic materials and polymers unites their advantages in osteochondral regeneration. With the addition of nano-HAP, the compressive strength was increased by more than two-fold compared to the CS/SF scaffold, with minor influence on degradation rate and facilitated cell adhesion and proliferation . PRP anded genes . As mosted genes . Seo et ed genes .There are approaches to extended use of platelet derivatives other than scaffold ingredients for bioactive upgrade and structural unity. For example, Brehm et al. use autologous PRP gel as an adhesive between the graft and the subchondral bone yet get little improvement in retention of the implant because of its poor mechanical strength and adhesion force .Successful attempts generally take advantage of bioactive molecules they content. As previously mentioned, platelet derivatives can be used as a culture medium supplement for CTE constructs before implantation for better cell proliferation, differentiation, and ECM accumulation . As the Derived from PRP treatment of knee OA, intra-articular platelet derivatives can be used as treatment adjuvants for improvement after transplantation. Once per 2 weeks intra-articular injection of PRP enhanced BMSC-laden collagen scaffold implantation, resulted in a higher level of chondrogenic differentiation markers and historical score . DominguBiological is a complex mixture of numerous bioactive molecules ideally functional in tissue regeneration. Although most of the main components of platelet derivatives have been independently studied in cartilage repair, the content of individual bioactive molecule varies depending on the protocol of extraction, format of the product, process of activation, and even health condition of the donor. Elucidation of the molecular complexity of these products and determining the dosing for specific tissue regeneration remain great challenges. The combination with biomaterials sustains the release of bioactive molecules and has made it even more complicated that both temporal and spatial distribution should be considered to meet the needs of developing CTE tissue and cells. Removal of defect components in platelet derivatives such as VEGF in cartilage diseases might be realized by “filter-like” advanced biomaterials or through an optimized extraction process . Recent In conclusion, the combination of platelet derivatives and biomaterials takes full advantage of the safe and low-cost resource of bioactive molecules that have been proved to accelerate cartilage regeneration and integration of neo-tissue and the origin parts. As variability is a common defect in biologicals, detailed information about platelet derivatives is required to maximize reproducibility of results. Further research of platelet derivatives in combination with biomaterials should aim to realize spatiotemporal delivery to meet the regeneration of articular cartilage, restore the function of the joint, and ultimately improve patients’ quality of life.


Dear Editor,Melanoma is a potentially lethal skin neoplasm that requires an accurate diagnosis to ensure that the patient will receive optimal treatment. Despite the advent of large-scale, high-resolution genomics, histopathological analysis remains the reference for diagnosis and the primary classification tool in correlation with clinical characteristicsMelanoma can exhibit a variety of histopathological patterns, mimicking other malignant tumors. Based on their histopathological characteristics, several morphological subtypes have been described in addition to the classical forms, such as polypoid, verrucous, desmoplastic, myxoid, balloon-cell, rhabdoid, amelanotic, and spitzoid melanoma, among othersOsteocartilaginous differentiation is characterized by the formation of osteoid, bone, and cartilaginous tissue by the neoplastic cells. Its rarity and overlapping characteristics with those of other neoplasms make it difficult to diagnose, especially in small biopsies or when clinical/radiological information is limited. It may be confused with osteosarcomas or chondrosarcomasThe mechanisms responsible for heterologous differentiation are not well understood. This report describes a case of melanoma with osteocartilaginous differentiation that developed on the distal region of the left upper limb.In August 2019, a 52-year-old woman came to the Orthopedics outpatient clinic with a history of a darkened lesion in the subungual region of the left thumb, with an evolution of approximately three years. On physical examination, edema, local phlogosis, and signs suggestive of fungal infection were observed. She underwent specific treatment for the infection but did not show a complete response.The subungual lesion was submitted to an incisional biopsy, and the histopathological and immunohistochemical study confirmed the diagnosis of melanoma. The patient was then referred to the Oncological Surgery service for specific treatment.2. After surgery, she had regular follow-up consultations at the Clinical Oncology department. After eight months, tumor growth was observed on the surgical scar. Computed tomography assessment showed a lesion suggestive of recurrence.In November of the same year, after evaluation, she underwent amputation of the affected finger. Histopathological analysis confirmed the diagnosis of nodular melanoma, with the presence of lymphovascular invasion and a proliferative index of 17 mitoses/mmShe underwent surgical resection once again, with en bloc removal of the lesion. Histopathological analysis of the specimen showed local recurrence of the melanoma, with the presence of vascular and neural invasion, in addition to compromised surgical margins. Follow-up imaging studies demonstrated the presence of axillary involvement and the presence of pulmonary lesions suggestive of metastasis.The patient was referred for adjuvant local and axillary radiotherapy in February 2021. She also started therapy with Dacarbazine and immunotherapy with Pembrolizumab in April 2021. In the same month, she had a new tumor growth in the area of the previous resection. Computed tomography showed extensive expansive/infiltrative soft tissue lesions in the distal region of the left arm and hand, and palliative surgery was chosen, with surgical disarticulation at the elbow and left axillary lymphadenectomy, performed in July 2021.Macroscopically, the surgical specimen showed a large tumor in the distal region of the left upper limb .Figure 1Histopathology showed the presence of melanoma with areas of heterologous osteocartilaginous differentiation , invadinDue to advanced and metastatic disease, the patient remained hospitalized, progressing with clinical worsening, signs of respiratory distress, and hemodynamic instability. With no possibility of disease-modifying therapy, she started exclusive palliative care, passing away in October 2021.Osteocartilaginous differentiation in melanoma was first observed over 45 years agoOsteoid, chondroid and mixed patterns have been described as appearing in predominantly acral and subungual sites. However, osteocartilaginous differentiation is not restricted to these regions, as it has been previously described in mucosal lesions, as well as in skin that is chronically or intermittently exposed to the sunThe mechanism for the formation of the osteoid/chondroid matrix in these melanomas is unknown. Many are associated with a history of previous local trauma and the osteoid/chondroid matrix may be a form of host response to the lesionHypothetical intrinsic melanoma factors that could drive the production of this matrix include the expression of the “Melanoma inhibitory activity (MIA)” and “Runt-related transcription factor 2” (RUNX2) genes, transcriptional regulators of chondrogenesis and osteogenesisAlthough these genes can be expressed by most melanomas, studies have already shown that MIA and RUNX2 require the expression of other cofactors to drive osteoid/chondroid differentiation, and the lack of these genes may explain the rarity of osteocartilaginous melanoma despite frequent gene expressionin situ” component, the presence of melanin pigment, or immunoreactivity with markers such as S100, Melan-A, HMB45, or SOX10The diagnosis of melanoma can be supported by the presence of an “In the molecular analysis, the presence of the V600E mutation in the BRAF gene can also support the diagnosis of melanoma, in addition to being crucial for planning its treatmentIt is not yet entirely clear whether the osteocartilaginous melanoma harbors only mutations and differentiation markers typical of melanoma or of the osteocartilaginous lesions it mimics as wellBased on the literature review, the authors highlight the importance of applying an immunohistochemical panel with the inclusion of melanocytic differentiation markers in cases of neoplasms with osteoid/chondroid differentiation, mainly in acral lesions, and of including melanoma with heterologous differentiation among the differential diagnoses. Due to the rarity of the case, the development of guidelines for early diagnosis, management and prognosis for this cancer variant remains challenging.None declared.Bennett Barroso de Carvalho: drafting and editing of the manuscript or critical review of important intellectual content; critical review of the literature.Diogo Batista dos Santos Medeiros: Effective participation in research orientation; drafting and editing of the manuscript or critical review of important intellectual content; approval of the final version of the manuscript.None declared.