Bioceramic materials with ion‐mediated multifunctionality for wound healing

Abstract Regeneration of both anatomic and functional integrity of the skin tissues after injury represents a huge challenge considering the sophisticated healing process and variability of specific wounds. In the past decades, numerous efforts have been made to construct bioceramic‐based wound dressing materials with ion‐mediated multifunctionality for facilitating the healing process. In this review, the state‐of‐the‐art progress on bioceramic materials with ion‐mediated bioactivity for wound healing is summarized. Followed by a brief discussion on the bioceramic materials with ion‐mediated biological activities, the emerging bioceramic‐based materials are highlighted for wound healing applications owing to their ion‐mediated bioactivities, including anti‐infection function, angiogenic activity, improved skin appendage regeneration, antitumor effect, and so on. Finally, concluding remarks and future perspectives of bioceramic‐based wound dressing materials for clinical practice are briefly discussed.


| INTRODUCTION
7][8] Current medical treatments like gauzes, bandages, cotton wools, and hydrophilic wound dressings commonly aim to provide a physical barrier to shield the wounds from contamination, maintain an appropriate level of humidity, absorb excess exudate at wound sites, and promote the healing process by delivering specific bioactive agents. 9,10However, these strategies have limited efficiency in healing large-scale injuries and chronic wounds, because they primarily depend on the slow and passive wound healing processes.2][13][14][15][16][17] These wound dressings may appear in different physical forms, such as films, sponges, foams, fibrous membranes, patches, hydrogels (sheets, bulks, or injectable ones), gels, creams, ointments, pastes, and so on. 18They usually contain antimicrobial drugs, antibiotics, anti-inflammatory agents, growth factors, cytokines, or other biological components including bioactive ceramic materials. 198][29][30][31][32][33][34] In this review, we will focus on the state-of-the-art progress on bioceramic materials with ion-mediated bioactivity for wound healing applications, as illustrated in Figure 1.Firstly, we will provide an overview of bioceramic materials with ion-mediated biological activities.Next, we will exemplify the current bioceramic-based materials for wound healing applications based on their ion-mediated bioactivities, including anti-infection function, angiogenic activity, the regenerative capacity of skin appendages, anti-tumor efficacy, and other multi-functions.Finally, we will provide concluding remarks and our insights into the bioceramic-based wound dressing materials for clinical practice.

| Overview of bioceramics
The term "bioceramic" is a general term used to cover glasses, glass-ceramics, and ceramics applied for graft implants and artificial scaffolds. 35More specifically, bioceramics typically possess nonmetal structures with high toughness and usually are prepared by sintering of inorganic compounds (e.g., metal oxides) in complex mixtures. 36Bioceramics have appeared as one of the most promising biomaterials for tissue engineering.The development of ceramic materials in biological applications has shifted from tissue replacement using bioinert ceramics (e.g., alumina, zirconia, and carbon or nitride-based ceramics) to tissue repair/regeneration using bioactive ceramics (e.g., bioglasses, bioactive glass-ceramics, calcium silicate, calcium phosphate, hydroxyapatite ceramics). 37,38The main characteristics of bioceramics include thermal and electrical insulation, high brittleness and hardness, corrosion resistance as well as good biocompatibility, biodegradability, and bioactivity. 39The bioactivity of bioceramic materials is mainly derived from their tendency to release inorganic ions that are involved in many biological processes. 18,24,26,40For instance, the Ca ion plays a significant role in regulating collagen formation and osteogenic differentiation, while Si and P ions are helpful for bone formation in F I G U R E 1 Schematic illustration of bioceramic materials with ion-mediated multifunctionality for wound healing.

Key points
� Recent progress on bioceramic materials with ion-mediated multifunctionality for wound healing.� Design strategies that are being used to develop bioceramic-based materials for wound healing.� Representative ion-mediated multiple functions, including anti-infection function, angiogenic activity, improved skin appendage regeneration, antitumor effect, etc. � Future challenges and perspectives that may lead to the development of bioceramic materials.
6][47] The architecture design of bioceramic-based materials at macro, micro, or nano levels is highly essential not only because they provide physical cues for cell-matrix interactions, but also because they have a great influence on the ionic dissolution rate of bioceramics and their ultimate biofunctions. 48

| Ion-mediated biological functionality
Bioceramic materials involved in wound healing mainly include noncrystalline bioactive glasses (BGs) and crystalline silicate or phosphate ceramics.Bioceramics are believed to play stimulatory roles in the skin regeneration process owing to their ionic dissolution products.As essential constant elements in the human body, silicon (Si) and phosphorus (P) exhibit positive effects on the formation of blood vessels (i.e., angiogenesis), collagen deposition, and epidermal regeneration during the wound healing process. 49Taking BGs as an example, BGs are classified based on their chemical composition into silicate bioactive glasses (SBG), phosphate bioactive glasses (PBG), and borate bioactive glasses (BBG). 18,35,50he amorphous glass networks facilitate the sustainable release of bioactive ions with the gradual degradation process of BGs in physiological environments.0][71][72][73] Mg ion plays a regulatory role in epidermal proliferation, differentiation, and skin barrier functions. 74,757][78] Cu ion is well-known for its significant role in angiogenesis by regulating the expression of proangiogenic factors such as vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) as well as the hypoxia-inducible factor (HIF-1α) to stimulate skin wound healing. 25,27,79,80In addition, Cu ion has antibacterial and anti-inflammatory properties.2][83] These ion-mediated biological effects of bioceramics make them an ideal choice for wound healing applications.It is worth noting that the biological effects of bioceramic ions function in a dose-dependent manner, and they may be toxic if used in a fairly high dose. 84,85

| Design of bioceramic-based wound dressing materials
Benefiting from their high bioactivities and multifunctionalities, the bioceramic materials can be either applied alone in the forms of fine powders or nanoparticle suspension, 27,80,86,87 or employed as the functional counterparts in composite wound dressing materials in the forms of bioceramic-incorporated hydrogels, 29,30,32,59,61,72,88,89 films or membranes, 28,31,33,53,[90][91][92][93][94][95] sponges, 73,96,97 porous 3D scaffolds, 25,52,54,98 and so on (Figure 3).For example, Zhao et al. prepared a kind of Cu-BBG microfibers with various Cudoping contents and evaluated their wound healing ability both in vitro and in vivo. 27The ionic dissolution products (e.g., Ca, B, and Cu ions) not only promoted migration, tube formation, and VEGF expression of human umbilical vein endothelial cells, but also stimulated the expression of several angiogenesis-related genes (bFGF, VEGF, and PDGF) of fibroblasts.Compared to undoped fibers, Cu-doped fibers showed an improved ability to promote angiogenesis for healing full-thickness skin defects in rats.For another example, Chen et al. coated the nanosized BBG with CO 3 2− -containing amorphous hydroxyapatite (HCA) to improve the biodegradability and biocompatibility of BBG (Figure 3A). 86Compared with the uncoated BBG powders, the nano-HCA@BG particles showed a controllable ion-release ability, contributing to the promoted cell proliferation in vitro and better skin wound healing effects in vivo.
When bioceramic particles/powders are directly applied to wound beds, their inherent brittleness and hardness are likely to induce acute inflammatory reactions and cell damage. 55,88,99In this regard, bioceramicbased wound dressing materials are more effective and flexible strategies for wound healing applications.For example, Cui et al. designed an organic-inorganic hybrid hydrogel with high-strength self-adhesive properties by incorporating hydroxyapatite (HAp) into the poly(Nacryloyl 2-glycine) (PACG) hydrogel networks (Figure 3B).The HAp not only strengthened the supramolecular polymer hydrogels by the ionic crosslinking of Ca 2+ ions to the carboxyl groups on the PACG chains, but also improved the biocompatibility and promoted wound healing with instant hemostatic effects. 72In tissue regeneration fields, it has been accepted that the porous scaffolds with nano/microscale biomimetic architectures could bring about a better tissue regeneration capacity for offering structural cues for new tissue ingrowth and construction. 53,54,100For example, Zhang et al. developed zinc-silicate-incorporated nanofibrous scaffolds via an electrospinning process (Figure 3C). 53The bioceramicnanoparticle-embedded nanofibrous scaffolds could maintain a sustained release of Zn and Si bioactive ions, which accelerated the formation of blood vessels and nerve fibers in second-degree skin burn defects.In another example, Ma et al. utilized strontium silicate (SS) particles as cell-induced factors for angiogenesis and integrated the particles into the cell containing bioprinting inks. 54Such bioceramic-containing multicellular biohybrid scaffolds exhibited excellent angiogenic activity and significantly accelerated skin wound healing in vivo (Figure 3D).
Given the significant characteristics mentioned above, such as good biocompatibility, biodegradability, flexible chemical formulation, ease of preparation, and tunable ion-mediated multifunctionality to accelerate wound healing, the bioceramics have attracted many researchers to employ them as multifunctional wound dressing materials for diverse wound healing applications.

| Anti-infection function
Skin acts as the first line of defense that protects internal tissues from the external damage and invasion of pathogenic organisms. 1016][107][108] Therefore, it is highly expected to develop new wound dressing materials with enhanced antimicrobial activity for wound healing.
Apart from the excellent tissue regenerative capacity, some bioceramic materials such as silicate or bioactive glasses possess intrinsic antibacterial activity owing to the alkaline microenvironment caused by the release of alkaline metal ions during their degradation process. 109,110However, such pH-dependent antibacterial activity is limited for an effective anti-infection functionality.2][113][114][115][116]  -containing hydroxyapatite (HCA)-coated BBG (nano-HCA@BG) and (ii) evaluation of the wound healing effect of nano-HCA@BG powders in mouse skin defects.Reproduced with permission. 86Copyright 2021, Elsevier.(B) Bioceramicsincorporated composite hydrogels: (i) Photographs showing the strong adhesion of the hydroxyapatite (HAp)-incorporated poly(N-acryloyl 2-glycine) (PACG-HAp) hydrogel to porcine skin under water flushing; and (ii, iii) SEM images showing the HAp nanoparticles uniformly dispersed in the PACG-HAp hydrogel networks.Reproduced with permission. 72Copyright 2018, John Wiley and Sons.(C) Bioceramicsincorporated electrospun membranes: (i) SEM images of zinc silicate (ZS) nanoparticles-incorporated poly(ε-caprolactone) (PCL) electrospun nanofibers; (ii) SEM image and corresponding EDS element mappings of (iii) element Zn and (iv) element Si of PCL+20ZS scaffolds.Reproduced with permission. 53Copyright 2022, John Wiley and Sons.(D) 3D printed bioceramics-containing scaffolds: (i) 3D printed strontium silicate-containing Gellan Gum hydrogel (SS-GG) scaffolds with various design patterns; (ii) SEM image of the surface of freeze-dried SS-GAM scaffold and corresponding EDS elemental mapping of (iii) element Sr, (iv) element Si, and (v) element O. Reproduced with permission. 54Copyright 2021, John Wiley and Sons.
hydrogel via double ion cross-linking of Ca 2+ and Zn 2+ to alginate polymer networks. 117Their results showed that the released Si ions from the composite hydrogel could promote new blood vessel formation and accelerate wound healing, while the released Zn ions inhibited the growth of bacteria.
In addition to the ion-induced antibacterial effect, photothermal therapy (PTT) has recently been utilized to kill bacteria via physical heating. 30,118,119In one case, a multifunctional composite hydrogel combined Cu-doped bioceramics with polydopamine (PDA) was designed for infectious skin wound healing. 120In this system, the photothermal heating effect of both PDA and Cu ions showed high efficiency and long-term inhibition of methicillin-resistant Escherichia coli and Staphylococcus aureus.Additionally, the Cu ion acted as a bioactive agent to stimulate angiogenesis for wound healing.Similar to Cu ions, Mo ions also exhibited an excellent PPT effect upon near-infrared (NIR) laser irradiation, which could be used for photothermal anti-infection therapy.For example, Lei group report a multifunctional bioactive Si-Ca-P-Mo glass-ceramic nanoparticle (BBGN-Mo or B-M) for effective infection therapy and skin wound healing (Figure 4). 30The Mo-containing bioceramic nanoparticles were prepared via a hydrothermal reaction between branched spherical BBGN and C 10 H 14 MoO 6 (Figure 4A).Compared with BBGM (B-0M), the BBGN-Mo displayed the following major functionalities: (i) excellent photothermal and antioxidant activity due to the existence of oxygen vacancies and free electrons (Figure 4B controlling the ratio of Mo 4+ to Mo 6+ (Figure 4D,E); (iii) effective antibacterial efficiency for infected wounds after surgery (Figure 4F-I); (iv) selective photothermal anticancer activity to inhibit the tumor reoccurrence without obvious side effect on healthy tissues for healing the tumor resection defects; and (v) a significantly higher wound healing rate in vivo with more skin appendage formation and enhanced re-epithelialization via releasing bioactive ions.

| Enhanced angiogenesis
][123] Enhanced in vitro and in vivo angiogenic capacity has been extensively demonstrated by the ionic dissolution products from bioceramic materials. 29,49,100,124,125For example, Chang group previously reported nanosized-SBG-coated hierarchically micro-patterned nanofibrous scaffolds for accelerating wound healing. 100The hierarchical micro/nanostructures of nanofibrous scaffolds together with the release of Ca, Mg, and Si ions from the SBG coating synergistically promoted angiogenesis, and improved in vivo wound closure rate and healing quality.Apart from amorphous glasses, bioceramic crystals such as Nagelschmidtite nanoparticles (Ca 7 P 2 Si 2 O 16 ) have been demonstrated effective for healing diabetic wounds by promoting vascularization, collagen synthesis, and epidermal regeneration. 49esides antibacterial effect, Cu ion is also known for its stimulatory role in angiogenesis. 25,27,79Cu-containing bioceramic materials have been incorporated into composite wound dressings and demonstrated effective for enhanced angiogenesis in wound healing applications. 28,55,80For example, Wu group previously used Cucontaining BGs to coat the eggshell membranes for both antibacterial performance and angiogenic capacity. 55heir results showed that the bioceramic-modified eggshell membranes could not only improve angiogenesis-related gene expression in vitro, but also accelerate the revascularization in vivo.More recently, we prepared a bioceramic-particle-incorporated electrospun membrane by using copper silicate hollow microspheres (CSO HMSs) as the source of Cu and Si ions for healing skin tumor-induced wounds (Figure 5). 28CSO HMSs were synthesized through a hydrothermal process and displayed a hollow microstructure with uniformly distributed O, Si, and Cu elements in the whole microspheres (Figure 5A-D).For wound healing application, we incorporated the CSO HMSs into electrospun fibrous scaffolds (Figure 5E) and further confirmed that Si and Cu ions could be gradually released from the CSOincorporated electrospun scaffolds (Figure 5F,G).The ion-mediated tissue regenerative bioactivity of such bioceramic scaffolds was demonstrated to accelerate diabetic wound healing in mice by promoting angiogenesis and re-epithelialization (Figure 5H-M).

| Stimulation of skin appendage regeneration
Intact skin is composed of the epidermis, dermis, and skin appendages, including hair follicles, sweat glands, and sebaceous glands. 126As skin appendages are essential for the biological and physiological functions of skin tissues, complete wound healing should include skin function recovery and structural integrity together with the regeneration of skin appendages. 127However, for adult mammals, wound healing typically results in scar tissues without skin appendages.][130] Bioceramic-based materials with ion-mediated bioactive properties have shown great potential in promoting optimal wound healing with the regeneration of skin appendages such as hair follicles.Recently, Chang group fabricated a series of bioceramic-incorporated electrospun fibrous scaffolds for stimulation of skin follicle regeneration. 33,56,57,94In one case, they integrated the cuprorivaite (CaCuSi 4 O 10 ) particles and quercetin (Qu) into electrospun fibers (Figure 6A). 94Bioactive Cu and Si ions as well as Qu-Cu chelates could be released from the composite membranes (Figure 6B,C), contributing to enhanced proliferative capacity of hair follicle dermal papilla cells (Figure 6D,E) and synergistic stimulatory effects on the hair follicle regeneration and skin tissue reconstruction (Figure 6F-H).Similarly, they also demonstrated the synergistic effect of Zn-Si 33,57 or Fe-Si 56 bioceramic incorporated biopolymer fibers to promote hair follicle regeneration during wound healing.

| Anti-tumor effect and simultaneous wound healing
Skin cancer is one of the most common frequent solid cancers with an estimated annual increase of 3%-7% in White populations. 131,1324][135] In this case, the large-sized skin wounds are difficult to heal, especially for patients with diabetes or other vascular diseases.Besides, the remaining tumor cells are likely to cause cancer recurrence. 92,98Therefore, it is desirable to construct bifunctional wound dressing materials to eliminate skin tumors and simultaneously to heal the tumor-induced wounds.
Over the past decades, bifunctional wound dressings based on a variety of metal elements (e.g., Cu, Fe, Mn, Eu, Gd)-meditated bioceramic materials have been designed for tissue regeneration and simultaneous tumor therapy like phototherapy (PTT or PDT). 31,32,61,87,89,91,93,136For example, Cu-containing bioceramics have been employed as photothermal agents owing to their efficient heat generation ability, which is derived from the d-d electron transition of Cu ions induced by NIR irradiation. 28,31,136In addition to the PPT effects, Fe-containing bioceramics could release Fe ions to catalyze the occurrence of Fenton reaction, thereby generating •OH to achieve tumor microenvironment targeted chemodynamic therapy. 89In our recent work, we proposed innovative bioceramic materials denoted as "black bioceramics," which extended the applications of traditional bioceramic materials from tissue regeneration to tumor therapy (Figure 7). 93The black bioceramics were synthesized from traditional white ceramics after magnesium thermal reduction.In our experiment, traditional phosphate-based (Ca 3 (PO 4 ) 2 , Ca 5 (PO 4 ) 3 (OH)) and silicate-based (CaSiO 3 , MgSiO 3 ) powders were transformed into black bioceramics, as shown in Figure 7A.Owing to the introduction of structural defects and oxygen vacancies after magnesium thermal reduction (Figure 7B-D), the black bioceramics could effectively release Ca and Si ions along with extra Mg ions in a controllable manner (Figure 7E-G).Notably, with the increasing Mg used in the reduction reaction, the obtained black bioceramic powders could gradually release more Mg ions but fewer Ca ions in specific periods.In addition, black bioceramics could be easily heated up under NIR irradiation at a low laser intensity (Figure 7H,I), resulting in excellent PTT therapeutic effects in skin-tumor-bearing mice (Figure 7J,K).Meanwhile, black bioceramic-based materials could significantly improve the tissue regenerative ability for skin wound healing in mice.These fascinating results indicated the feasibility of using single black bioceramic materials for tumor therapy and tissue regeneration, which not only extends the biomedical potential of bioceramics, but also represents a promising direction for multi-functional biomaterials.

| Other multi-functions
8][139] Recently, engineered Janus amphipathic wound dressings have been developed with anti-adhesion abilities and unidirectional water transfer  94 Copyright 2020, American Chemical Society.1][142] Besides wound drainage, it is also necessary for stimulating angiogenesis in chronic wound healing.Therefore, Bao et al. designed a multifunctional composite wound dressing membrane, consisting of a modified Janus membrane with a BG-containing bioactive layer for promoting angiogenesis and a superabsorbent layer for effective water absorption during wound healing. 95ompared with traditional Janus membranes, this modified Janus membrane showed unique bi-directional fluid transport properties, which allowed large amounts of exudate to be pumped from wounds rapidly while a small number of bioactive ions transported back to wound beds.
More recently, smart wound dressings have been developed to monitor the change of physical and chemical parameters at wound sites, including humidity, temperature, pH, reactive oxygen species, enzymes, growth factors, etc. 14,143 In one case, Chang group reported a multifunctional bioceramic-based composite hydrogel dressing for determining the optimal temperature in vivo during PTT tumor elimination via Nd-ionmediated fluorescence thermometry, and simultaneously healing the heat-damaged normal tissues by releasing bioactive Ca and Si ions (Figure 8A). 59They first prepared Nd-doping calcium-silicon-based bioactive ceramic (Nd-BG) materials, which had unique photothermal effects and fluorescence characteristics different from non-Nd-doping CS-BG (Figure 8B,C).Subsequently, they incorporated the Nd-BG glass into an alginate composite hydrogel and determined the optimal PTT temperature at 53°C in mouse tumor models (Figure 8D).Under this safe temperature, the tumor was completely eliminated without causing damage to surrounding normal tissues.In addition, the composite hydrogel could release bioactive ions to repair the PTT-damaged tissues.This study suggested that bioceramic materials with photothermal function, wound healing bioactivity, and unique temperature monitoring may satisfy the multifunctional needs of practical wound treatments.

| SUMMARY AND OUTLOOKS
In this review, we provide a brief summary of the state-ofthe-art progress on bioceramic materials with ionmediated bioactivity for wound healing applications.We first make a critical discussion on bioceramic materials with ion-mediated biological activities.Next, we highlighted the emerging bioceramic-based materials for wound healing applications owing to their ion-mediated bioactivities, including enhanced angiogenesis, antibacterial activity, improved skin appendage regeneration, anti-tumor effects, and other multi-functions.Such multifunctional bioceramic-based materials have emerged as one of the most promising wound dressing materials in clinical aspects, and the ion-mediated wound healing strategy is anticipated to extend the use of bioceramic materials in skin tissue regeneration from the laboratory into the clinic.Since the first bioactive glass invented by Larry Hench in 1969, commercial products derived from bioactive ceramics have been used clinically to treat bone-or tooth-related issues. 35,63For example, the bioactive glass S53P4 has been successfully used in clinic as an antibacterial bone substitute with bone-bonding and osteostimulative properties, 144 and more interesting, it has been reported effective to accelerate wound healing in a follow-up study. 145DermFactor® is a silicatebased wound dressing widely used for wound management in burned skin, diabetic foot ulcers, and bedsores.A clinical study of DermFactor® has been conducted to evaluate its wound healing efficacy after anal surgery. 146t is found that the postoperative wound healing was significantly accelerated after the treatment of Derm-Factor®, which did not induce any adverse reaction to the patients.These clinical outcomes suggest that the bioceramic-based biomaterials can be suitable wound dressing in practical clinical applications.
Although with many successes as we reviewed, current research on bioceramic-based wound healing materials is far from mature and there are still many challenges ahead in developing bioceramic materials and their practical applications in skin tissue regeneration.Firstly, the physicochemical and biological properties of the final wound dressing products are dependent on the selection of bioceramic materials and the corresponding fabrication methods of the wound dressings.Current bioceramic-based wound dressings are mostly prepared by simple physical blending methods.The covalent bonds between the bioceramic particles and the dressing matrix are rarely considered.In addition, the distribution and stability of bioceramics within the matrix are hardly under control.New fabrication technologies should be developed by taking advantage of the interactions between bioceramic ions and matrix molecules, which is important for tailoring whole material systems for practical wound healing applications.Besides, more multifunctional bioceramic-based wound dressings should be designed with optimized multiple compositions, since it is difficult to impart multiple functionalities using a single-component system in practical applications.Furthermore, more attention should also be paid to revealing the underlying mechanisms of both the single ion-mediated bioactivity and the synergistic effect of different ion combinations on their regulation of different types of cells, which will ensure further progress on bioceramic-based materials and offer new research opportunities in wound healing applications.Last but not least, the long-term in vivo safety certification of bioceramic materials should be systematically demonstrated before consideration for practical applications in clinics.Overall, the above issues will be addressed with the tremendous efforts made in biomaterials for tissue engineering.The bioceramic materials with ion-mediated multifunctionalities are believed to be exploited to overcome current challenges in wound healing applications and ultimately achieve clinical transformation.
For example, Li et al. prepared an bioactive hardystonite (Ca 2 ZnSi 2 O 7 ) ceramic-incorporated F I G U R E 3 Representative bioceramic-based materials used for skin wound treatment.(A) Bioceramic particles or powders: (i) Preparation of nanosized CO 3 2− ,C); (ii) photothermal performance with "biocompatible photothermal temperature" achieved by F I G U R E 4 Bioceramic-based wound dressings for effective infection therapy and skin wound healing.(A) Synthesis and structure illustration of BBGN-Mo (B-M) with multifunctional activities.(B) High-resolution TEM of B-M (blue pane: CaMoO 4 nanocrystal, yellow pane: MoO 2 nanocrystal).(C) XPS spectra of Mo 3d of B-M.(D) Real-time infrared thermal images of B-M samples.(E) Photothermal heating curves (808 nm) and photographs (inset) of various B-M samples at 1 mg/ml.(F) Photographs of MRSA-infected skin wounds during 14 d of treatment with different samples under an NIR irradiation for 10 min.(G) Changes in wound size after various treatments (n = 6).(H, I) Wound tissue-derived bacteria colonies (H) and corresponding statistical data of colonies (I) against MRSA after incubation for 3 days (n = 6).*p < 0.05; **p < 0.01.Reproduced with permission.30Copyright 2021, American Chemical Society.

F I G U R E 6
Bioceramic-based wound dressings for hair regeneration in burned skin.(A) SEM images of the quercetin (Qu) and bioceramic (CaCuSi 4 O 10 ) incorporated (P/Qu/Cup) electrospun composite fibrous membranes.(B, C) Release of Si and Cu ions and Qu in P/Cup, P/Qu, and P/Qu/Cup composite membranes.(D, E) Proliferation of human hair follicle dermal papilla cells (HHDPCs) cultured with (D) Qu-Cup composite fiber membranes and (E) Qu/Cup extracts.(F) Schematic illustration of hair follicle regeneration process.(G) Number of hair follicles on Day 24.**p < 0.01, n = 6.(H) Images of immunohistochemical staining for cytokeratin 19 on Day 10, 17 and 24.HF indicated the newly-formed hair follicles.Reproduced with permission.

F I G U R E 7
Black bioceramic-based wound dressings for photothermal tumor therapy and wound healing.(A) Photographs of black CaSiO 3 (BMCS), MgSiO 3 (BMMS), Ca 3 (PO 4 ) 2 (BMCP), and Ca 5 (PO 4 ) 3 (OH) (BMHAP) powders prepared by magnesium thermal reaction with increasing contents of Mg powders as compared to the pristine white bioceramics.(B, C) High-resolution TEM image and corresponding geometric phase analysis (GPA) of white CaSiO 3 (WCS) (B) and BMCS (C) bioceramic powders.The white arrows indicate the presence of misfit dislocations.(D) High-resolution XPS spectra of Si 2p for WCS and BMCS powders.(E-G) Cumulative amounts of Ca (E), Mg (F), and Si (G) release at each time point from various black BMCS bioceramic powders treated with different amounts of Mg (i.e., BMCS1, BMCS2, BMCS4, BMCS6, and BMCS8) into Tris-HCl solution at 37°C.(H) Real-time infrared thermal images and (I) corresponding heating curves of BMCS, BMMS, BMCP, and BMHAP bioceramics as compared to the pristine white bioceramics (WCS, WMS, WCP, WHAP) under NIR irradiation.(J) Representative photographs of skin wounds in skin-tumor-bearing mice on days 0, 3, 6, 9, 12, and 15. (K) H&E staining of sectioned skin-tumor-induced skin wounds from different groups on day 15.Reproduced with permission. 93Copyright 2020, John Wiley and Sons. 10 of 15 -WANG AND TANG

F I G U R E 8
Multifunctional bioceramic-based wound dressings for in situ temperature monitoring, photothermal therapy, and wound healing.(A) Schematic showing the injectable Nd-Ca-Si bioglass/alginate composite hydrogel for in vivo tumor elimination, determining optimal PTT temperature by fluorescence thermometry and repairing heat-damaged normal tissues by releasing bioactive Ca and Si ions.(B) Heating curves of the Nd-BG2 and CS-BG composite hydrogels under 808-nm laser irradiation.(C) Linear fitting relationship between 1062-nm fluorescence intensity and temperature for Nd-BG2 composite hydrogels.(D) H&E staining images of skin tumor tissues after different temperature treatments (blue arrow, tumor tissues; red arrow, fibroblasts; yellow arrow, inflammatory cells; green arrow, new blood capillary).Reproduced with permission.59Copyright 2020, The Authors, published by AAAS.