1. Introduction
Tissue damage is regarded as one of the most intractable health problems because of its high morbidity and high cure difficulty [
1], [
2], [
3], [
4], [
5], [
6]. Thus, great scientific efforts have been dedicated to achieving the repair of damaged tissue by remodeling tissue and restoring its biological function [
7], [
8], [
9], [
10]. In this aspect, the integration of biomaterials-based scaffolds with tissue engineering opens up new avenues for tissue-damage repair due to such scaffolds’ good biocompatibility and ideal cell adhesion [
11], [
12], [
13], [
14], [
15], [
16]. Although much progress has been achieved in this area, the therapeutic effects remain unsatisfactory because the available scaffolds are generally incongruent with damaged tissues with irregular shapes and have insufficient oxygen for cell proliferation [
17], [
18], [
19]. In contrast, biomedical microparticles from microfluidics have emerged as promising candidates for tissue-damage repair, as microfluidics enable the extensive design of components and functions, and the tiny products generated in this way provide infinite options for adapting to the damaged area [
13], [
20], [
21]. However, most of the microparticles from microfluidics are spherical and prone to displacement under external forces, which is adverse for wound healing [
22], [
23], [
24]. Furthermore, these microparticles generally deliver drugs in a single mode and the release profile is poorly controlled, which is not conducive to tissue regeneration [
25], [
26], [
27]. Therefore, the development of new microparticles for tissue regeneration is still anticipated.
In this paper, inspired by erythrocytes-associated self-repairing process in damaged tissue, we present novel biomimetic erythrocyte-like microparticles (ELMPs) for promoting tissue regeneration by using microfluidic electrospray (
Fig. 1). As the most abundant cells in the blood, erythrocytes act as cargo carriers to deliver oxygen and other molecules in order to maintain life [
28], [
29], [
30]. In the tissue self-repair process, erythrocytes can also play critical roles by providing adequate oxygen to facilitate cell proliferation and tissue remodeling [
31], [
32]. Moreover, as erythrocytes possess a special biconcave discoid morphology and mechanical flexibility, they exhibit the advantages of a large specific surface area and stacking stability [
30], [
33], [
34], [
35]. Furthermore, it has been demonstrated that discoid microparticles with the morphology of erythrocytes benefit cell adhesion and proliferation [
36], [
37], [
38], [
39], [
40]. Thus, the outstanding advantages of erythrocytes in terms of both structure and function provide a valuable reference for tissue regeneration. However, the translation of such a compelling idea into practical therapy for tissue damage remains unexplored.
Herein, we employed a microfluidic electrospray technology to fabricate the desired ELMPs and demonstrated their value in promoting the regeneration of damaged tissues. These ELMPs, which had components similar to those of the extracellular matrix (i.e., polysaccharide and recombinant collagen), were formed by the in situ crosslinking of deformed viscoelastic droplets from a microfluidic electrospray system. Black phosphorus (BP), hemoglobin (Hb), and growth factors (GFs) were integrated into the components during the fabrication, endowing the resultant ELMPs with near-infrared (NIR)-responsive GFs release and the capacity of oxygen delivery, both of which benefit cell adhesion and stimulate angiogenesis. It was demonstrated that, when applied to damaged tissues, the proposed ELMPs could overlap to fill the wound and remain stable based on their unique morphology. In addition, the ELMPs could realize controllable cargo release to achieve the expected curative effect on the damaged tissue by promoting extracellular matrix secretion and angiogenesis. These results confirmed that our biomimetic ELMPs were ideal for tissue regeneration, thanks to their discoid morphology and cargo-delivery functions, indicating their great potential in tissue engineering.
2. Materials and methods
2.1. Materials, cell lines, and animals
Kappa-carrageenan (KC) and recombinant human collagen (RHC) II were purchased from Shanghaiyuanye Bio-Technology (China) and Jiangsu JL and Biotech Co., Ltd. (China), respectively. 1-(3-dimethylaminopropyl)-3-ethylcarbondiimide (EDC), N-hydroxysuccinimide (NHS), methacrylic anhydride (MA), and 2-hydroxy-2-methylpropiophenone (HMPP) were obtained from Sigma-Aldrich (USA). Vascular endothelial GF (VEGF) and fibroblast GF (FGF) were supplied by PeproTech (USA). Fluorescein-isothiocyanate-labeled bovine serum albumin (BSA-FITC) was bought from ZhongKeChenYu (Beijing) Biotech Co., Ltd. (China). Phosphate-buffered saline (PBS; pH = 7.4) was bought from Biosharp (China). The NIH 3T3 cell line and human umbilical vein endothelial cells (HUVECs) were supplied by the Cell Bank of the Chinese Academy of Sciences (China). Methyl thiazolyl tetrazolium (MTT) was bought from Thermo Fisher Scientific (USA). 2-(N-morpholino)ethanesulfonic acid (MES) buffer (pH = 6.0) was self-prepared. Antibodies of CD31 were obtained from Servicebio Technology Co., Ltd. (China). Male Sprague-Dawley (SD) rats (250 g in weight) were supplied by Drum Tower Hospital (China). The Animal Investigation Ethics Committee of Southeast University examined and approved all animal handling and experimental programs (20230726002). All applicable institutional and/or national guidelines for the care and use of animals were followed.
2.2. Fabrication of Methacrylate-esterified RHC hydrogel
Methacrylate-esterified RHC (RHCMA) was fabricated by reacting RHC with MA, according to a previous reported method [
41]. In brief, freeze-dried RHC was dissolved in PBS at room temperature to prepare a 10% (w/v) RHC solution. Then, 0.5 mL of MA was added dropwise into 10 mL of RHC solution, and the pH value of the solution was restricted to between 8 to 9 using 1 mol∙L
−1 NaHCO
3. After reacting for 1 h, the final solution was dialyzed in a dialysis membrane (14 kDa cutoff molecular weight) for five days. The pH value of the dialyzed solution was regulated to 7.2, and the final RHCMA sponge was obtained by lyophilizing.
2.3. Fabrication of ELMPs and characterization
A uniaxial microfluidic electrospray device was employed to fabricate the ELMPs. Precursor solution loaded in a syringe was pumped into the capillary through a hose. The precursor solution contained KC, 20% (w/v) RHCMA, and BP (0.2 mg·mL−1). HMPP was used as the photo-initiator and was added into the precursor solution at a volume ratio of 1%. An aqueous gelling bath containing 2% (w/v) potassium chloride (KCl) was placed directly under the nozzle and exposed to ultraviolet (UV) light. The collected ELMPs were washed with PBS 20 times to completely remove the HMPP and KCl. The deformation process of the ELMPs was captured by a high-speed camera. Optical images of the ELMPs were captured using an optical microscope (JSZ6S, Jiangnan Novel Optics Co. Ltd., China) installed with a charge coupled device (CCD) camera. Scanning electron microscope (SEM) images were imaged using a field-emission SEM (Ultra Plus, Zeiss, Germany).
2.4. Photothermal conversion test
The ELMPs were arranged into a square matrix with the dimensions 1 cm × 1 cm on a slide. Focused light from a NIR laser (808 nm) was used to vertically irradiate the ELMPs, such that the irradiation area just covered the ELMPs. To obtain the most suitable power level, varied power was applied to irradiate the ELMPs and the temperature changes were recorded per 10 s via a hand-held thermal imager (FLIR Systems Inc., Sweden). For the photothermal conversion stability test, a cyclic test was carried out by turning the NIR laser on for 1 min and then off for the next 2 min; this was consecutively repeated five times.
2.5. Biodegradation test
The ELMPs were incubated in PBS, which was replaced once a day [
42]. ELMPs were collected, freeze-dried, and weighed every three days. The degradation ratio was shown as a percentage of the measured weight relative to the initial weight. The biodegradation of the ELMPs in trypsin solution was tested using a similar method in which the ELMPs were incubated in trypsin solution (2.5 μg·mL
−1) [
43]. Furthermore, another two groups of ELMPs were irradiated by a NIR laser twice a day to investigate the influence of NIR by adopting the same method.
2.6. Visualization of protein modification
In brief, the ELMPs were incubated in MES buffer solution dissolved with EDC and NHS at 37 °C for 30 min to activate the carboxyl group. The ELMPs were then collected, cleaned with PBS, and transferred into the BSA-FITC solution (1 mg·mL−1) for incubation overnight to attach the protein to the ELMPs. As a comparison, another group of ELMPs was directly immersed in the BSA-FITC solution (1 mg·mL−1) for incubation overnight. Subsequently, the two groups of ELMPs were washed 20 times using free PBS, which lasted for five days. The cleaned ELMPs were observed under an inverted fluorescence microscope.
2.7. Hb modification of ELMPs and oxygen-release test
The Hb was coupled into the ELMPs by forming an amide linkage with the RHCMA hydrogel. The carboxyl groups on the RHCMA were activated by EDC and NHS in MES buffer solution, and then the treated ELMPs were washed several times using free PBS and immersed in Hb solution (2 mg·mL−1) for incubation overnight. The fabricated Hb-modified ELMPs (ELMPs@Hb) were then collected and washed. For oxygen loading, the ELMPs@Hb were immersed in oxygen-rich PBS overnight to uptake oxygen. Nitrogen was passed into free PBS overnight to remove the dissolved oxygen (DO) in advance, obtaining fresh PBS without oxygen. The ELMPs@Hb were quickly cleaned three times using the fresh PBS and collected to be incubated in fresh PBS in an anoxic environment. The oxygen-release data was measured after 0, 1, 2, 4, 8, 12, and 24 h of release by measuring the DO concentration of the PBS using a DO meter. The oxygen pressure was converted from the measured concentration of DO.
2.8. Drug-release test
BSA-FITC was chosen as the model drug for macromolecule protein drugs. First, 1 mg of freeze-dried ELMPs was immersed in BSA-FITC solution (1 mg·mL−1) overnight to fully load the model drug. The ELMPs loaded with BSA-FITC were then quickly washed three times with free PBS. The cleaned ELMPs were then collected and immersed in 1 mL of free PBS for incubation at 37 °C. The solution of 100 μL was collected as a sample at a predetermined time point, and the same amount of free PBS was added after sampling. The fluorescence intensity of the samples was measured, and the measured values of fluorescence intensity were converted to the concentration of BSA-FITC according to the corresponding relationship between fluorescence intensity and concentration of BSA-FITC solution. Thus, the cumulative amount of BSA-FITC released from ELMPs was calculated.
2.9. Biocompatibility in vitro
The experiment included four groups: the ELMPs group, ELMPs@Hb group, ELMPs@Hb + NIR group, and control group. A 48-well plate was employed to culture NIH 3T3 cells (about 104 cells in every well) and incubate them with ELMPs and ELMPs@Hb, a process that lasted for three days. The control group was cultured normally, and the ELMPs@Hb + NIR group was irradiated by NIR twice a day. The cell viability of each group was tested daily by adding MTT into the wells to form formazan and recording the optical density (OD) value of dimethyl sulfoxide (DMSO) dissolved with the formed formazan. In addition, on the third day, Calcein-AM was added into the wells to stain the live cells. The ELMPs and ELMPs@Hb in the wells were sucked out and observed under an upright fluorescence microscope, while the cells in the wells were observed under an inverted fluorescence microscope.
2.10. In vitro tube-formation experiment
Oxygen, VEGF, and FGF were co-loaded to obtain the final ELMPs + drugs for testing. The groups were the same as in the previous experiment. GFs-induced Matrigel of 100 μL was used to carpet each well of a 48-well plate and was solidified at 37 °C. HUVECs (3 × 104 per well) were seeded in each well to be cocultured with ELMPs + drugs and ELMPs, for 8 h, respectively. Calcein-AM was added into each well to stain the cells, and the tubular structure that emerged was observed under an inverted fluorescence microscope. The data of the total tube length was normalized to the control group.
2.11. Animal experiment in vivo
A bilaterally partial defect of the ventrolateral muscle with the dimensions 1 cm × 1 cm in the abdominal wall was created by excising the external muscles and preserving the peritoneum and transversalis muscle of SD rats. The experiment involved four groups: the ELMPs group, ELMPs + drugs group, ELMPs + drugs + NIR group, and control group. PBS, ELMPs, and ELMPs + drugs were respectively applied to completely fill the space where the muscles were missing. After implantation, the skin was sewn together using 3-0 vicryl interrupted sutures. Thermal images of the damaged area were recorded using a thermal imager. For the ELMPs + drugs + NIR group, the damaged tissues were irradiated by NIR twice a day. All rats were sacrificed after a fortnight, and the repaired abdominal walls were harvested.
2.12. Histological evaluation
The repaired abdominal walls were embedded into paraffin and sliced with 5 μm. Hematoxylin and eosin (H&E) staining was employed to show the granulation tissue thickness and inflammation. Masson’s staining was used to evaluate the collagen deposition and tissue formation, while immunohistochemical staining of CD31 was used to evaluate blood vessel formation.
2.13. Statistics analysis
All count data were represented as mean values ± standard deviation. One-way analysis of variance (ANOVA) and the Tukey post hoc test were applied to evaluate the statistical significance of each pair of groups. The difference between groups was considered to be reliable only when p < 0.05.
3. Results and discussions
In a typical experiment, a uniaxial microfluidic electrospray device was employed to fabricate the ELMPs. The precursor solution injected into the microfluidic electrospray device contained KC, RHCMA, and BP. RHCMA was synthesized through a substitution reaction between RHC and MA to obtain
in situ UV-crosslinking capability (Fig. S1 in Appendix A) [
41]. The precursor solution was broken into microdroplets at the nozzle under the applied electric field. An aqueous gelling bath containing 2% (w/v) KCl was exposed under UV light to collect and crosslink the dropped microdroplets. When they came into contact with the solution interface, the droplets were deformed along with simultaneous crosslinking, undergoing both the ionic crosslinking of KC and UV crosslinking of RHCMA to form ELMPs (
Fig. 2(a)). More specifically, due to the weak gel capacity and high viscosity of the KC, the fluid of the spherical droplets tended to spread from the middle to the edge upon coming into contact with the solution interface to form discoid microparticles. The spreading was stopped by the subsequent complete crosslinking of KC and the
in situ photo-crosslinking of RHCMA. ELMPs bearing a uniform discoid morphology were captured by an optical microscope, as shown in
Figs. 2(b) and
(c). SEM images were obtained to further confirm the discoid morphology of the microparticles from the cross section and side view, both of which showed the porous structure as well (
Figs. 2(d) and
(e)). A distribution analysis of the particle size also indicated that the resultant ELMPs were uniform particles (
Fig. 2(f)).
In addition, unlike spherical particles, the discoid morphology of the ELMPs allows them to stack together (Fig. S2 in Appendix A). The size of the ELMPs could be adjusted by changing both the external electric field and the flow rate during microfluidic electrospray. In general, a smaller microparticle could be collected under the conditions of a lower flow rate and higher applied voltage (
Fig. 2(g)). Notably, the proportion of KC played a critical role in the formation of the discoid morphology. Our own experiments on the influence of KC concentration have shown that a very low concentration (lower than 0.2% (w/v)) causes the microdroplets to change into an irregular shape and stick together. This occurs because the low degree of crosslinking in the KC network causes over-dispersion of the droplets, and the diffusion of RHCMA through the solution cannot be restricted prior to photopolymerization. With an increase in the KC concentration, the morphology of the crosslinked microparticles gradually became universally discoid and monodispersed (Fig. S3 in Appendix A). The concentration of KC was limited to less than 0.5% (w/v) so that the suitable viscosity of the precursor solution could prevent size heterogeneity of the generated microdroplets. In addition, the concentration of RHCMA was chosen to be 20% (w/v) to ensure adequate mechanical strength.
Collagen, which is the main component of the extracellular matrix, has many active sites that can be chemically modified. The derivative RHCMA retained an extracellular matrix-like structure and provided the ELMPs with abundant sites for chemical modification. As an example, BSA-FITC was coupled to the ELMPs to visualize its protein modification via carbodiimide-based chemistry (Fig. S4(a) in Appendix A). The final fluorescence image of the ELMPs confirmed the excellent feasibility of protein modification, granting them great potential for customized design for biomedical purposes (Fig. S4(b) in Appendix A). Moreover, the integration of BP endowed the ELMPs with a photothermal responsive capacity, which enabled controllable drug release under NIR light. Notably, the upper temperature threshold was limited to around 39 °C to prevent burns to the surrounding tissue and further thermally induced changes in the properties of the hybrid hydrogels. It was found that NIR light of 1.43 W·cm
−2 could rapidly raise the temperature of the ELMPs to 39.2 °C within 1 min; the ELMPs would then cool to room temperature within the next 2 min (
Fig. 3(a)). Five consecutive cyclic tests demonstrated the stability of the photothermal responsive heating behavior in response to NIR irradiation, as recorded in
Fig. 3(b).
Furthermore, Hb was integrated into the ELMPs by means of carbodiimide-based chemistry to give the ELMPs an oxygen-delivery capacity and avoid the toxic side effects of free Hb (Fig. S4(c) in Appendix A). The oxygen-delivery capacity of the ELMPs@Hb was subsequently determined by measuring the DO concentration of the PBS containing the oxygen-loaded ELMPs@Hb. It was observed that the ELMPs@Hb performed an obvious adjustment of the oxygen pressure, including oxygen loading under oxygen-rich conditions and oxygen release in an oxygen-lacking environment. Intriguingly, the release process was tunable under NIR irradiation (
Fig. 3(c)). More specifically, the increase in temperature caused by NIR irradiation led to a faster and greater oxygen release due to the decrease in the oxygen-binding capacity of the Hb [
21]. Overall, we have successfully obtained ELMPs@Hb with an erythrocyte-like morphology and the oxygen-delivery characteristics of erythrocytes.
To verify the drug-delivery performance of our ELMPs, the drug-delivery capacity of the ELMPs was investigated. Water-soluble BSA-FITC was taken as the typical model drug and was loaded into the ELMPs via soaking, followed by immersion in PBS to visualize the general drug-release profile of the functional protein molecules. Based on NIR-triggered photothermal conversion, the ELMPs were expected to realize regulation of the release process. As expected, it was observed that the ELMPs conducted sustained drug release, with faster release when irradiated with NIR light at repeated intervals (
Figs. 4(a) and
(b)). These results indicated that the NIR-responsive release behavior of ELMPs could be remotely and repetitively controlled under NIR. Such controllable release characteristics pave the way to intelligent drug delivery.
Considering that the self-degradation and biocompatibility of the materials are of great importance in tissue regeneration, we investigated the degradation and biocompatibility of the ELMPs
in vitro. For the degradation test, ELMPs with or without NIR irradiation were incubated in PBS and trypsin solution, respectively, to examine their stability under storage conditions and to simulate biodegradation in a cellular-like environment. It was observed that the ELMPs still retained 96.9% of their weight in PBS and 74.2% in trypsin solution. The degradation process was accelerated under NIR, but the ELMPs still retained 95.4% in PBS and 67.4% in trypsin solution (
Figs. 4(c) and
(d)). These results indicated that ELMPs could serve as
in vivo implantable materials with excellent stability during the functional period and subsequent self-degradation to avoid the risk of secondary surgery. For the biocompatibility test, the ELMPs and ELMPs@Hb with or without NIR irradiation were incubated with NIH 3T3 cells to verify their biocompatibility. Cell viability was tested by using a MTT assay and normalized to the percentage of the control group on the first day. The results showed that the 3T3 cells could grow and proliferate as normal. Calcein-AM was used to stain the live cells to check the cell morphology and observe the cell behavior on the surface of the ELMPs and ELMPs@Hb. Cell test
in vitro are shown in
Fig. 5. No visible changes were observed in the cell morphology of the 3T3 cells, and the cells were able to proliferate normally when adhered to the ELMPs and ELMPs@Hb (
Figs. 5(a) and
(c); Fig. S5 in the Appendix A). These results indicated that the ELMPs had good biocompatibility and excellent potential for use as a biological microscaffold for cell adhesion and proliferation.
During the practical self-repair process of tissue, in addition to the adequate oxygen required to meet the metabolic demands of damaged tissues, endogenous functional molecules (e.g., GFs) are needed to interact with the cellular receptors
in vivo in order to accelerate the regeneration of damaged tissues [
44]. Thus, oxygen and functional GFs, including VEGF and FGF molecules, were co-loaded into the ELMPs@Hb for the synergistic treatment of damaged tissues. The angiogenic properties of the ELMPs@Hb with GFs and O
2 (ELMPs + drugs) were tested
in vitro. HUVECs were selected to be incubated with the ELMPs + drugs. When the cells were induced by VEGF, they were able to proliferate and migrate to form a vascular-like structure, which was a tube structure surrounded by HUVECs. It was found that the ELMPs + drugs + NIR group exhibited the best vascular-like tube structures, indicating that more GFs could be released from the ELMPs + drugs under NIR and that their biological functions were preserved (
Figs. 5(b) and
(d)).
Finally, a muscle defect of abdominal wall model, a typical animal model of damaged tissues, was established
in vivo to further assess the feasibility of the ELMPs + drugs for tissue engineering. A partial square in the muscle with the dimensions 1 cm × 1 cm was excised on each side of all the rats, as shown in Fig. S6(a) in Appendix A. Then, the rats were randomly grouped into three equal groups: the ELMPs group, the ELMPs + drugs group, and the ELMPs + drugs + NIR group. ELMPs and ELMPs + drugs were respectively implanted on the right damaged areas of the rats from different groups (Fig. S6(b) in Appendix A). All the left damaged areas were set as the control group. After successful implantation, the cut skins were sutured (Fig. S6(c) in Appendix A). Then, the photothermal conversion of the ELMPs was first examined
in vivo. Thermal images of the damaged areas were recorded to examine the temperature changes in the differently treated tissues after NIR irradiation. The results showed that the local temperature of the ELMPs-filled area rose to about 39 °C after 1 min, which was clearly higher than the temperature increase in the control group (
Figs. S6(d)-(f) in Appendix A). These results indicated that the desirable photothermal conversion effect of the ELMPs could be retained
in vivo with little attenuation due to the strong light penetration of the NIR laser through the whole skin.
After a fortnight, the skin incisions were opened and the regenerated tissues were cut off to evaluate the repair performance in each group by means of histological analysis. From the results of the H&E staining, as shown in
Fig. 6(a), there was no significant infiltration of the inflammatory cells in the regenerated areas of all four groups, demonstrating the excellent biocompatibility of our designed microcarriers. Moreover, the thickness of the granulation tissues in the ELMPs + drugs group and ELMPs + drugs + NIR group was significantly greater than that in the control group and ELMPs group (
Fig. 6(a); Fig. S7(a) in Appendix A). The ELMPs + drugs + NIR group had the best granulation tissue thickness, which could be attributed to the promoted therapeutic release. It is worth noting that the ELMPs group had a relatively obvious promoted repairing effect compared with the control group. This was because the ELMPs could be arranged to fit the wound’s irregular shape in order to protect the wound from external harm, serving as a three-dimensional biocompatible scaffold for cell adhesion and proliferation.
Subsequently, the new collagen deposition and angiogenesis surrounding the damaged tissue area were visualized by means of Masson staining and immunohistochemical staining of CD31 to assess the tissue remodeling. In
Fig. 6(b), a greater expression of collagen, stained blue, indicated promoted extracellular matrix secretion and thus was regarded as achieving a better repair effect. CD31 is a marker of vascular endothelial cells and can be stained to observe neovascularization. The newly formed vessels played a critical nutrient-delivery role, while the greater density of vessels permitted better regeneration. As shown in
Figs. 6(b) and
(c), there was much more extensive collagen deposition and angiogenesis in the ELMPs + drugs and ELMPs + drugs + NIR groups compared with the other two groups, indicating a more powerful tissue-repair capability. This result can be ascribed to the regenerative-promoting capacity of the GFs and oxygen released by the ELMPs + drugs. Notably, the best collagen deposition and greatest vessel density occurred in the ELMPs + drugs + NIR group, demonstrating that promoting the therapeutic release could accelerate the regeneration process (Fig. S7(b) in Appendix A). The regeneration performance of the ELMPs treatment was better than that of the control group, indicating that the ELMPs could act as a microscaffold to promote tissue regeneration. Therefore, the ELMPs + drugs performed multiple functions to promote tissue restoration in the damaged tissue area, indicating their great potential in further tissue engineering.
4. Conclusions
In conclusion, we presented novel NIR-responsive ELMPs and developed them into therapeutic and oxygen-loaded ELMPs + drugs for tissue regeneration. The incorporation of BP made it possible to adjust the release profile of the ELMPs + drugs; meanwhile, an oxygen-delivery capacity was endowed by coupling Hb to the RHCMA hydrogel. The ELMPs + drugs exhibited great biocompatibility and could serve as a microscaffold for maintaining cell proliferation. Overall, the proposed ELMPs + drugs integrated the discoid morphology and oxygen-delivery functions of erythrocytes with the novel drug carrier/microscaffold of hydrogel microparticles for tissue engineering. When applied to repair the damaged abdominal wall in a rat model, the ELMPs + drugs realized definite promotion of extracellular matrix secretion and neovascularization to accelerate tissue regeneration. The photothermal conversion of the ELMPs + drugs was also demonstrated to be triggered under NIR to promote therapeutic release and achieve a better curative effect. Thus, the responsive therapeutic-delivering ELMPs + drugs exhibited excellent potential for the fields of tissue engineering and provided an innovative concept for the design of novel drug microcarriers/scaffolds.
Acknowledgments
This work was supported by the National Key Research and Development Program of China (2020YFA0908200), the National Natural Science Foundation of China (T2225003, 52073060, and 61927805), the Nanjing Medical Science and Technique Development Foundation (ZKX21019), the Clinical Trials from Nanjing Drum Tower Hospital (2022-LCYJ-ZD-01), the Guangdong Basic and Applied Basic Research Foundation (2021B1515120054), and the Shenzhen Fundamental Research Program (JCYJ20190813152616459 and JCYJ20210324133214038).
Compliance with ethics guidelines
Zhiqiang Luo, Lijun Cai, Hanxu Chen, Guopu Chen, and Yuanjin Zhao declare that they have no conflict of interest or financial conflicts to disclose.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.eng.2023.08.022.
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