Introduction

Biopolymers derived from renewable sources are abundant in nature, biocompatible, inexpensive, and degradable without leaving any toxic residues, which prime characteristics of biopolymers to be an ideal candidate for biomedical applications [1, 2]. Due to their biodegradability and nontoxicity, biopolymers attained much attention used in liver and cardiac tissue engineering and wound healing as hydrogel, powder, and films in tissue engineering [3,4,5]. Natural bio-organisms such as bacteria, fungi, algae, etc. help to promote the degradation or break down via aerobic or anaerobic processes into small molecules leaving behind some organic by-products such as CO2, H2O, etc. [1]. Besides their excellent attributes, the structures of biopolymers resemble the structure of extracellular matrix (ECM) macromolecules which allow them to be compatible and functional appropriately within the host. Natural polymers include chitosan, starch, carrageenan, agar, alginate, etc. from plant carbohydrates and whey protein, soy protein, gluten, collagen, zein, casein, gelatin, etc., from plant or animal protein origin. These polymers have been used vastly in drug delivery, such as encapsulation, solid monolithic matrix systems, beads, microparticles, scaffolds, nanoparticles, as well as inhalations and injectable systems and viscous liquid formulations [6,7,8]. The polymeric material plays the role as matrix or drug release modifiers, viscosity modifiers, binding agents, film coating substances, disintegrating agents, solubilizing agents, emulsifying agents, suspending agents, gelling agents, and bioadhesives [9]. Biodegradable polymers derived from starch are suitable for drug delivery in the form of the microcapsule, microsphere, implants, or hydrogel. It does not require any surgery to remove the device after drug depletion [10]. Synthetic biopolymers include poly(l-lactic acid) (PLA), poly(e-caprolactone) (PCL), poly(glycolic acid) (PGA), poly(vinyl alcohol) (PVA), poly(butylene succinate) (PBS), etc. are also garnered much attention in biomedical fields [5]. And finally, biopolymers produced through microbial fermentation include microbial polyesters, such as poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PBHV), poly(hydroxyalkanoates) (PHAs), poly(β- hydrocxybutyrate) (PHB), etc., and microbial polysaccharides including curdlan and pullulan are also applied for biomedical applications. Synthetic biodegradable polymers like poly(α-hydroxyesters), polyanhydrides, and polyorthoesters, have found more versatile and diverse biomedical applications owing to their tailorable designs or modifications and extensively used for fabricating tissue engineering matrices [11]. Biopolymer-based scaffolds can regenerate damaged tissue and organs in the host body and promote healing tissue regeneration process. These scaffolds have drawn much attention for engineering tissues such as skin, cartilage, vascular, bones etc., as they offer suitable conditions for the tissues, cells, and organs to disintegrate and proliferate effectively [12,13,14,15]. The scaffold should meet some essential criteria to be a promising candidate for biomedical application such as biocompatibility, biodegradability, nontoxicity, non-inflammatory, nonimmunogenic, structural integrity, optimal porosity, sound mechanical and physiological properties [8, 14, 16, 17]. During the regeneration process, the scaffolds serve as an alternative three-dimensional structure of ECM and allow an appropriate environment for tissue regeneration. Application of biopolymer-based scaffolds would be helpful to minimize some unavoidable side effects of non-biocompatible polymers’ implants, such as chronic inflammation, immunological activity, and toxicity within the body.

Recent advances in modern biotechnology regarding cell regeneration with the aid of signal molecules are promising techniques in biomedical applications. Smart biomaterial research has triggered the necessity to develop smart biopolymer scaffolds for biomedical applications. For the breakthrough in the biomedical field, this review focuses on the background and recent advances of natural-based biopolymer scaffolds’ application in the following sections: (1) drug delivery, (2) tissue engineering, (3) wound healing, and finally, both natural and synthetic in (4) miscellaneous biomedical applications. Special emphasis has been given to the applications of biopolymers in drug delivery, tissue engineering, infections, and wound healing applications, which indicate the advancement and employment of the various biopolymers in recent biomedical applications. Lastly, this review addresses some recent challenges which need to be considered to make existing scaffolds more useful in future applications.

Classification and Attributes of Biopolymers

Depending on the origin of raw materials (extracted from natural resources such as starch, sugar, cellulose, and fossil oil), biopolymers can be categorized into three broad groups such as (1) natural, (2) synthetic, and (3) microorganism-based biopolymers [1, 18]. The natural resources of producing biopolymers comprise microorganisms, plants, and animal tissues and can also synthesize from aerial, terrestrial, and marine living organisms. For example, microorganisms such as bacteria, fungi, yeasts, molds, smuts, and many other forms of what a primitive life is can be very potential to offer an enormous variety of polymeric biomolecules with outstanding structural and biochemical attributes. These biopolymers comprise polysaccharides such as cellulose, chitin, chitosan, dextran, chitin, hyaluronic acid, etc., and proteins like silk, keratin, etc. Plants have been a precious and renewable source of both polysaccharides and proteins for a long time. Animals are also a potential source, whether highly developed or not, whether they live on the land, sea, or air can provide natural structures with strong potential in the biomedical field. Examples of these structures comprise glycosaminoglycans (chitin, hyaluronic acid, etc.), proteoglycans, and proteins (collagen, elastin, gelatin, etc.) with the addition of deoxyribonucleic acid, the genetic material instigated from all living sources [19].

Based on the monomeric unit present and the structure, natural biopolymers can be classified into three types: polynucleotides, polypeptides (proteins), and polysaccharides [19,20,21]. The nucleic acid is a generic biological material consisting of a large number of molecules in sequence. These are polymers having nucleotides as monomer units. There are two types of nucleic acids, DNA and RNA. These are linear polymers having smaller molecules (monomers unit) attached in sequence. Several nucleotides are linearly linked by covalent bonds to form polynucleotides. A nucleotide molecule is composed of three distinct molecules: five-carbon sugar, a phosphate group, and a nitrogenous base, as shown in Fig. 1. In DNA and RNA polynucleotide biopolymer, a nucleotide monomer has a phosphate group and bonded to the sugar of the next nucleotide monomer, making a chain having a regular sugar-phosphate group [22]. In DNA, the sugar molecule is deoxyribose, but in RNA, it is ribose. Also, DNA biopolymer usually has a double-stranded chain, whereas RNA has linear chains of α-amino acids. A combination of polypeptide molecules results in the formation of proteins [19]. The amino acids are covalently bonded with the help of peptide bonds. The individual amino acid linked in the protein chain is called a residue, and the linked chain of nitrogen, oxygen, and carbon is called the protein backbone (Fig. 2). The picture shows how three amino acids are linked by peptide bonds forming polypeptides.

Fig. 1
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A nucleotide monomer showing phosphate, sugar, and nitrogenous base group

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Fig. 2
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Structure of protein. Reprinted with permission [19]

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Proteins can be extracted from a wide variety of materials, including wool, leather, silk, gelatin, and collagen. Differ in the sequence of amino acids make a lot of varieties of proteins. Proteins have essential roles in living organisms include immune responses, cell adhesion, and cell signaling. Polysaccharides are long chains (linear or branched) of monosaccharide units bonded together by glycosidic linkages, but upon hydrolysis release the constituent of monosaccharides or oligosaccharides. Examples of polysaccharides include storage polysaccharides such as starch and glycogen and structural polysaccharides such as cellulose and chitin [20]. Pattanashetti et al. explained the smart biopolymeric materials, which have the property to respond to significant changes due to small changes in the environment. They referred to them in the category of environmentally sensitive polymers. They classified smart biopolymers into three categories: pH-sensitive smart biopolymers, thermosensitive smart biopolymers, and stimuli-responsive biopolymers [20].

Riedel et al. classified biopolymers into three categories—polymer chain, polymer, and monomer [23]. Polymer chain biopolymers are naturally synthesized polymers such as carbohydrates, proteins, polyphenol resin, etc. Polymer category biopolymers are biotechnologically synthesized polymers like polyhydroxybutyrate and co-polyesters. The third type is naturally synthesizing monomer unit polymers such as plant oil and derivatives from sugar. Rebelo et al. classified the biopolymers into four categories, as mentioned in Table 1.

Table 1 Classification of biopolymers [21]
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Recent technological advancement enables the vast application of biopolymers in the medical field and can be categorized into drug delivery applications, wound dressing and healing materials, tissue engineering, biomedical sensors, surgical scaffolds, etc. Controllable drug release in our bodies can be accomplished easily using biodegradable polymer encapsulation. In wound healing, highly biocompatible nonwovens can be used to replace human tissue and simple sutures, staples, clips, or meshes are also available. Most of the biopolymers exhibit good film-forming behaviors, making them appropriate in high-performance applications and in traditional commodity uses. Biopolymer based nonwovens can also be used in agriculture, filtration, hygiene, and protective clothing.

Promising Areas of Biopolymer Applications

Biopolymers play versatile roles in various functionalities in the human body such as embrace cells to form tissues and provide signals to the cells to control their behavior. They also moderate the skin’s hydration and elasticity to maintain a natural environment. They make all joints and gastrointestinal tracts flexible via lubrication and protect from pathogens through accumulating into the mucus gel which covers human eyes and respiratory tract [20]. In addition, biopolymer-based scaffolds do a lot of works such as signal transportation to monitor cell behavior, maintaining skin’s hydration and pliability, protecting from pathogens and maintaining joints flexibility through lubrication etc. This section discusses the promising application areas of biopolymers and their composites with challenges, state-of-the-art methods, and innovation in carriers.

Drug Delivery

The controlled release of a therapeutic agent in a tunable dose is the most fundamental requirement for any drug delivery system that can be accomplished with a successful conjugation between a therapeutic agent and a drug delivery vehicle [9, 24,25,26,27]. However, the coupling of a drug with a delivery agent depends on the chemical structure (that can be both hydrophilic or hydrophobic) of the drug molecules; hence, rational design of a drug delivery agent must be required for a successful conjugation [26, 28, 29]. Furthermore, the drug carrier must inhibit any enzymatic degradation of a therapeutic agent before its controlled release. After a successful delivery, the drug carrier must be possessed non-toxicity, biodegradability, and most importantly, it should release from the body without any side effect [9, 30, 31]. In general, polymeric materials are an excellent candidate for acting as a drug delivery agent. However, bio-polymer and its derivative showed better properties such as ease of functionality, water-solubility, non-toxicity, biodegradability, and biocompatibility [21, 32]. Moreover, these biopolymers can reduce drug toxicity with a controlled drug release. They also reduce any enzymatic degradation before releasing a therapeutic agent in the target sites. Releasing of therapeutic agent can be triggered by various stimuli such as physical (sonophoresis, temperature, light, magnetic or electric field), chemical (biochemical, hypoxia or pH), environmental or combination of more than one stimulus (as shown in Fig. 3). In this context, biopolymers are promising materials as drug delivery agents. Polysaccharides, polypeptides, and proteins are three major classes of biopolymers that are extensively using as drug delivery systems.

Fig. 3
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Controlled therapeutic agent release based on different stimuli-response triggered by the physical, chemical, or environmental process. In general, external stimuli can be dominated by physical processes such as light, sound, heat, magnetic, or electric fields. Stimuli-responsive functional groups or grafting of nanoparticles on the polymeric system are commonly employed for external stimuli. Chemical or environmental processes are usually used for internal stimuli with pH, hypoxia, and selective functional groups (responsive to a specific biochemical process of the body system) of the polymeric system. Reprinted with permission [221]

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Carbohydrate molecules consist of long-chain monosaccharide or disaccharide unit covalently linked with glycosidic linkage are known as a polysaccharide. Plants (starch, hemicellulose, cellulose, agar, glucomannan, pectin, guar gum, and gum acacia), microbes (curdlan, gellan, dextran, xanthan), algae (alginate, carrageenan), and fungae (chitin, pullulan, scleroglucan) are the major source of polysaccharide [33,34,35,36]. Most of them are neutral or possess a negative surface charge. Only chitin can have cationic polysaccharides. However, functionality is one of the major advantages of polysaccharide molecules, which can control the overall drug delivery systems. Different types of drug vehicle systems such as micro/nanocapsules, micro/nanosphere, polymer-drug conjugation, micelle, liposome or hydrogel formation are the most common drug delivery system where therapeutic agents must disperse or encapsulate in the biopolymer matrix [37,38,39,40].

Chitosan (CH), prepared via N-deacetylation of chitin, is the only cationic polysaccharide that is most widely used in different types of drug delivery systems [41,42,43,44,45]. Nowadays, CH can be successfully used in the oral, vaginal, nasal, parental, or injectable route. It is well known that CH is compatible with living tissue; hence it must reduce enzymatic degradation. It is also reported that drug diffusion from the chitosan matrix can be controlled for tunable doses. Moreover, drug absorption and stabilization in the polymer matrix are other advantages for chitosan-based drug delivery systems [46]. Chitosan-drug conjugation is one of the most successful drug delivery systems where different types of chitosan molecular weight were used for this conjugation formation and cleaving condition can be pH or GSH (glutathione) sensitive based on the drug types [46, 47]. Hydrogel formation with chitosan is another approach for any sensitive protein or gene delivery [44, 48, 49]. Because some genes or proteins are susceptible to be damaged in contact with organic solvents or body fluids. Therefore, the cationic chitosan can form hydrogel with the presence of polyanion such as tripolyphosphate (TPP); hence, strong ionic cross-linking can form strong gelation that can protect genes or proteins till the controlled drug released in the target active sites [50,51,52].

Cellulose is the most abundant biopolymer with excellent mechanical and biological properties such as biocompatibility, biodegradability, and low cytotoxicity [53]. Cellulose with different aspect ratios such as microcrystalline cellulose (MCC), cellulose nanomaterials (CNC and CNF) and bacterial nanocellulose (BNC) are common classes of materials that are excellent candidates for drug delivery systems [54,55,56,57]. However, bacterial nanocellulose (BNC) is the most promising material compared to other types of cellulose due to its excellent biocompatibility with different shapes (such as spheres, tubes, fibrous, aggregates, fleeces, or foils) that can be controlled with its biosynthesis route. Moreover, without showing any severe signs of inflammation or toxic response at the cellular level, in vivo or in vitro biocompatibility of BNC can up to 1 year compared to other types of cellulose systems [58]. Chemical modification such as etherification, esterification, phosphorylation, or amidation is commonly applied in BNC for incorporating any diffusion barrier, which significantly modifies the drug release rate [56, 59,60,61,62].

Collagen is the most abundant protein from the animal kingdom that consists of a triple helical structure of glycine–proline–hydroxyproline repeating unit. Due to their excellent biocompatibility, it has been using in drug delivery application as microparticle, coating, films, or hydrogels [63,64,65,66,67]. Denatured collagen (gelatin), as well as collagen with a binding protein, can deliver therapeutic agents ranging from small molecules to biomacromolecules (DNA, protein, or even cells). Sometimes collagen might combine with liposomes where a therapeutic agent must be encapsulated inside the liposomes. This collagen with the liposomes approach may improve both drug release rate and therapeutic efficiency. Collagen corneal shields, contact lenses known as BioCora collagen shields, also have potential applications for water-based conjunctival antibiotics and corticosteroids such as Vancomycin, Amphotericin-B, pilocarpine, Gentamycin, bacterial and HSV keratitis [67,68,69].

Grafting of smart polymers on the biopolymer surface or biopolymer composites is also using for drug delivery systems [70, 71]. Drug diffusion rate, inhibition of enzymatic degradation, altering the pH-responsive range or hydrogel formation is commonly achieved with the composite systems [72, 73]. Grafted BNC-g-poly (acrylic acid) hydrogels showed extended pH-responsive drug delivery compared to the pristine BNC system due to changes in surface chemistry [74]. Composite hydrogel system such as alginate in BNC scaffolds demonstrates a prolonged drug release rate due to intermolecular drug-drug interactions [74, 75].

Tissue Engineering Applications

Tissue engineering is the most attractive approach that deals with repairing and regenerating biological tissues substituting by biopolymer composites implants. One of the prime requirements of biopolymer composites to be an ideal scaffold in tissue engineering and regenerative medicine is mimicking the collagen-rich extracellular matrix (ECM) that supports the structural and biochemical. The classical cell culture, growth and proliferation can be enhanced by mimicking the physical and biochemical nature of tissues in vivo by reconstructing the original structure of ECM applying scaffolds having similar surface topography.

Hard Tissue Scaffolds

In tissue engineering, necessity of hard tissue scaffolding is raising for different medical application such as bone fractures and cartilage [76,77,78], imperfections [79], joint replacements [80, 81], bone plates, bone cement [82], artificial ligaments [83], and tendons [84,85,86,87] & dental implants [88]. Human bone is a complex ordered tissue having ~ 69% hydroxyapatite (HAP) (bio-ceramics), ~ 21% collagen (natural polymer), 9% moisture, and 1% other ingredients [89]. The human bone is a complex bio-composite structure, called the ECM (Fig. 4) associated with the musculoskeletal system of the body. The healing process of an injured bio-composite system is linked to a lot of factors such as the regeneration of the tissue, biocompatibility, low toxicity, bio-absorbability, bio-mineralization, and maintaining suitable mechanical strength [90,91,92]. Now biomaterials such as protein (collagen) and polysaccharides (chitosan, silk, alginate, starch, and bacterial cellulose) are used with hydroxyapatite to generate a functional bio-composite anticipated to regenerate the natural tissues with proper biomechanical performance, including biomineralization.

Fig. 4
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Extracellular matrix (ECM) of human bone. Reprinted with permission [222]

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Collagen is the most abundant, most studied, and critical structural protein found in the ECM of vertebrate tissues. Collagen is a triple-helical structure of a large protein that formulated an essential part of natural tissue scaffolds in mammals [93]. Recently, several studies have been performed and exploited on the collagen-based composite to regenerate bone tissue [94, 95]. In Fig. 5, an example of collagen/HAP composite obtained from O'Brien’s literature [96] confirming the successfully incorporated collagen protein into the HAP matrix.

Fig. 5
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A Composite of the collagen-HAP scaffold with uniform distribution of HAP particles (Green) [96] B flexible collagen-HAP viscoelastic composite [223], Reprinted with permission Gleeson et al. [110] reported that collagen/(0–200 wt%) HAP composite could attain better biocompatibility, cell-mediated mineralization (0.01–0.2) including biomechanical performance (0.4–1.4 kPa) (Color figure online)

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Table 2 shows the structural properties and biocompatibility of collagen/HAP composite that are summarized from literature with varying % of HAP.

Table 2 Structural properties and biocompatibility of collagen/wt% HAP (X)
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Both native [97,98,99] and modified collagen [100, 101] are used in several studies with HAP [102] for bone tissue regeneration. Apart from collagen, other biopolymers such as chitosan [103, 104], silk fibroin [105], alginate [106], starch [107], bacterial cellulose [108], and cross-linked cellulose nanocrystal (CNC) aerogels [109] are also used as a natural polymer with hydroxyapatite filler. All these biopolymers are well studied for both biocompatibility and mechanical response for particular applications. In Fig. 6, the HAP composite containing different biopolymer are summarized. As seen from Fig. 5, the composite structures are mostly porous structures which are required for the biocompatibility and bio-regeneration process. Moreover, optimized mechanical properties are also obtained through the HAP filler effect. The main drawback of biopolymer has a lower mechanical response, and on the other hand, the only HAP can hinder the bio-regeneration process. It is possible to overcome this problem using different optimized biopolymer composite to regenerate the bone tissue [96].

Fig. 6
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SEM micrograph of biopolymer-based HAP composite for hard tissue regeneration containing A chitosan [103], B silk fibroin [105], C alginate [106], D starch [107], E bacterial cellolose [108] and F crosslinked cellulose nano crystal (CNC) aerogels [109], Reprinted with permission

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Soft Tissue Scaffolds

The second category of biological tissue substitution deals with soft tissue scaffolds application. Neural tissues are mainly known as the soft tissues having stiffness values 0.1–1 kPa for brain parts and 230 kPa for the spinal cord [114, 115]. It includes nerves, muscles, ligaments, tendons, skin, blood vessels, lungs, cartilage, intervertebral discs, fat, etc., which function simultaneously with the connected body organs [114,115,116]. These tissues can be injured by disease, age, inherited defects, traumas resulting in malfunctions, disfigurement, or death. The structural properties and composition of scaffolds should match with the host natural ECM system to help cell growth and tissue regeneration in the applied area [117, 118]. Besides, scaffolds must be biocompatible with host tissue, transport nutrients within the cell matrix, porous enough to support cell accommodation.

In the past, several polymeric materials have been used to fabricate tissue scaffolds, which are distinguished into two broad classes: (i) natural and (ii) synthetic and their derivatives. Natural polymer includes proteins like collagen [119, 120], gelatin [121,122,123], elastin [124], prolamine [125], fibrinogen [126, 127] etc.) and polysaccharides which are cellulose [128, 129], alginate [130, 131], chitin [132], chitosan [17, 133], dextran [134] etc. are broadly used in soft tissue engineering. Alternatively synthetic polymer includes polyurethane (PU) [135, 136], poly(vinyl alcohol) (PVA) [137], polyacrylamide (PAM), polylactic acid (PLA) [5], polyglycolic acid (PGA), polycaprolactone (PCL) [138], polyhydroxyethyl methacrylate (pHEMA), poly(ethylene glycol) (PEG), polyethylene oxide (PEO), poly(acrylic acid) (PAA), and poly(propylene fumarateco-ethylene glycol) P(PF-co-EG) and their copolymers [139, 140]. Both the polymers are excellent candidates for the fabrication of tissue scaffolds due to their biodegradability, biocompatibility with low cytotoxicity, ability to transport nutrients and imitate host natural ECM.

The application of collagen-based scaffolds in soft tissue engineering has garnered much attention during the last decades. As a natural polymer, collagen possesses excellent properties to be successful as an excellent candidate for soft tissue engineering listed in Table 3. Collagen is the key part of ECM of soft, semi-rigid, and rigid connective tissues and responsible for ensuring not only the 3D structure but also for the growth of new tissues. Collagen, being an amphoteric macromolecule, the interaction between molecules, fibrils, and chain fragments due to intramolecular attraction, dipole–dipole, or hydrogen bonds, can form gels in the aqueous system at a pH outside of the isoelectric range. Besides the gels, collagen-based hydrogels exhibit superior structural and thermal properties, longevity, and biological properties due to the 3D polymeric networks established through cross-linking of gels. The three-dimensional structure guarantees the stability and physical integrity of the hydrogels. Natural bonding via cross-linking in vivo offers high structural integrity and strength and proteolysis resistance to collagen. Physical and chemical cross-linking are the two main types of in vitro methods to get collagen hydrogels. However, extensive cross-linking exhibits some drawbacks such as it can change the physical integrity of the hydrogels structure and cytotoxicity due to some chemical cross-linkers (e.g. glutaraldehyde). Grant et al. showed enhanced longevity of collagen constructs through decreasing the degradation rate of collagen while maintaining the microstructure [141]. They developed AuNPs induced collagen constructs and found that it exhibits only 7% degradation or loss of collagen compared to 100% degradation of pristine collagen via collagenase binding sites. They implanted the AuNP-collagen cohort into the subcutaneous space of swine ears and performed up to 6 months in vivo study. The implanted cohort exhibits superior biocompatibility and longevity compared to commercially available Hyaluronic acid (HA) induced collagen cohort. It can be attributed due to the conjugation of AuNPs to collagen fibrils allowing slow degradation through hindering collagenase binding sites.

Table 3 Summary of some recent reported collagen-based scaffolds
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Gelatin is another naturally derived polymer with low antigenicity compare to pristine collagen due to having degraded collagen. Gelatin can be used to construct various kinds of structures with superior stability and cell adhesion [148]. Gelatin-based scaffolds are promising candidates for tissue engineering due to the extensive viability, differentiation, and propagation of cells shown in Table 4. Kessler et al. developed methacrylated gelatin/hyaluronan scaffolds to investigate their interaction with human stem cells (hASCs) [8]. They photo-crosslinked methacrylated gelatin gels using crosslinker (lithium phenyl-2,4,6-trimethylbenzoylphosphinate) with hyaluronan to make the hydrogels. They used the hydrogel to examine the cell viability and adipose disintegration of ASCs for up to 30 days and observed satisfactory cell viability within 24 h. They found mature adipocytes due to adipogenic differentiation of ASCs and increased significantly until 28 days of culture. This can be due to the phenomenon that imitation of ECM composition and constant supply of foods to proliferated cells results in excellent cell viability, proliferation, and differentiation. Negrini et al. engineered gelatin-based hydrogels with varying structural properties using different concentrations and reaction parameters during the fabrication process [149]. To imitate the properties of adipose tissue (AT), the fabricated hydrogels should possess a wide range of properties to regenerate different AT depots. They developed four different (15GEL05, 15GEL1, 25GEL05, and 25GEL1) types of hydrogels using crosslinker like N–N′-methylene bis(acrylamide) (MBA) and different gelatin concentration (15 or 25% w/vwater) and/or their ratio during the fabrication process. The synthesized hydrogels showed elastic modulus ranging from 29 to 76 kPa, which is appropriate to imitate breast and heel pad AT. Among the above four hydrogels, 15 GEL05 showed superior results mimicking breast AT with no cytotoxic effects.

Table 4 Summary of some recent reported gelatin-based scaffolds
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Elastin is the prime functional protein for most of the elastic tissue like skins, lungs, muscles, ligaments, tendons, blood vessels, etc., and plays a role in their physiological activities. Besides elastic properties, elastin needs to have structural stability, bioactivity, and biocompatibility for tissue engineering application. Pesqueira et al. (2018) introduced a unique approach to stimulate intrinsic healing tissue regeneration by using the strength of a magnetic field [155]. They developed magnetically responsive tropoelastin (soluble precursor of elastin) hydrogels induced with highly discrete nanoparticles in the matrix. The hydrogel showed high sensitivity (about 5 s) with the applied external magnetic field to trigger the healing capability without changing the elasticity of the materials. The fabricated hydrogel exhibits high cell cultural increased (p < 0.0001) activity compared to the control system (tropoelastin alone) after 14 days of incubation. This study widens the application area of elastin protein including, wound healing, cell growth in the injured area.

Plant proteins also offer some excellent properties which make them promising candidates for soft tissue scaffolds precursors such as readily available, biodegradable, non-toxic, amphiphilic nature, antimicrobial effect, high morphological and structural properties etc. Vogt et al. used zein, plant protein with poly (glycerol sebacate) (PGS) to fabricate soft tissue scaffolds for cardiovascular tissue regeneration or reconstruction [125]. They electrospun zein-PGS fiber mats to imitate ECM structure to overcome the drawbacks of donor site morbidity, foreign body response, malformation, complications etc. They found that the zein-PGS fiber showed limiting mechanical improvement in aqueous solvent whereas fiber induced with N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide(EDC)/N Hydroxysuccinimide (NHS) exhibits enhanced mechanical and morphological properties.

Alginate polysaccharide is another abundant natural polymer widely used for cell encapsulation as well as in vivo cell, drugs, protein delivery. Researchers have done tremendous studies on alginate embedded hydrogels for cell regeneration. But most of the alginate hydrogels possess degradation problems as in vivo application. To tackle this limitation, researchers tried to develop alginate hydrogels induced with cross-linking agents to enhance mechanical integrity and stability. Deepthi et al. developed alginate nanobeads fibrin hydrogel through calcium cross-linking with high material integrity and showed mechanical strength of 19 kPa [130]. This injectable hydrogel offers high material integrity, high surface area, improved growth factor and cell delivery. The excellent biocompatibility behavior of alginate gel was investigated via hMSC viability and adhesion test. They observed outstanding cell retention behavior of the developed hydrogel as well as cell growth and proliferation. As it is the prerequisite of soft-tissue scaffolds to possess mechanical integrity and compatibility with the application field, alginate-based hydrogel mimics the elasticity and strength of the soft tissue that made them an excellent candidate for soft tissue regeneration and reconstruction. Markstedt et al. developed human chondrocytes scaffold via a 3D bioprinting technique using alginate and nanofibrillated cellulose (NFC) hybrid hydrogel for soft tissue application [156]. The fast cross-linking behavior of alginate and shear thinning properties of NFC made possible this 3D bio-ink printing. The cytotoxic and cell feasibility test ensures the 3D printed scaffold is an outstanding candidate for the growth of cartilage tissue. They observed promising cell viability of the scaffolds of 73% and 86% after 1 and 7 days of culture. This is due to the excellent biocompatibility and potential media for cell culture of the alginate/nanocellulose hydrogel.

Carboxymethyl cellulose (CMC), another form of regenerated cellulose, is an excellent candidate for biomaterials application due to its outstanding chemical properties listed in Table 5. But CMC showed some difficulties via polyelectrolyte complex formation during nanofiber formation, which limits its application. To overcome this drawback, Basu et al. fabricated CMC/PEO (polyethylene oxide) nanofibrous scaffolds through electrospinning technique for soft tissue engineering applications [3]. The higher charge density of CMC/PEO solution favors forming nanofibrous scaffolds via electrospinning technique. The fabricated scaffold showed promising cell proliferation, non-toxic, and metabolic activity, which implies their potential applications in tissue engineering.

Table 5 Summary of some recent reported alginate-based scaffolds
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Chitosan, a deacetylated derivative of chitin, is one of the most prominent biomass polysaccharides, possesses excellent biocompatibility, biodegradability, nontoxicity, and adsorption properties. Though chitosan-based scaffolds have so many promising properties for numerous applications, including biomedical, tissue engineering, drug delivery etc., listed in Table 6 but low mechanical strength restricts its wide applications. Researchers tried to enhance the structural strength of chitosan-based scaffolds (Fig. 7) by blending them with other synthetic or natural polymers reported in the literature [119, 163]. Polyurethane is one of the most extensively used synthetic polymers in the biomedical field due to its outstanding biocompatibility with high physical and mechanical properties. Oliveira et al. fabricated a chitosan-based bilayered scaffold with hydroxyapatite (HA/CS), having optimized structural integrity and strength for osteochondral application [164]. The fabricated scaffold exhibited outstanding cell viability, propagation, and differentiation of osteoblasts and chondrocytes, respectively. These results widen the application area of chitosan in the field of biomedical and tissue engineering applications.

Table 6 Summary of some recent reported chitosan-based scaffolds
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Fig. 7
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Chitosan-based scaffolds for soft tissue engineering; first column-classical view, middle column-surface morphology and third column-cross-sectional view of chitosan-xanthan gum, Ch-X (A–C), Ch-X porous scaffolds, Ch-X-S (D–F), Ch-X with surfactant Kolliphor (10% w/w), Ch-X-K10 (G–I), Ch-X-S-K10 (M–O), and Ch-X-S-K25 (P–R) formulations. Reprinted with permission [119]

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Wound Healing

The vertebrate body’s largest organ is the skin, which provides the principle exterior defense system against external attacks such as contamination, infection, and the effect of harsh external environments. Besides protecting its role in sensory detection, regulating body temperature, fluid homeostasis, and self-healing is also crucial. Skin is usually composed of three parts such as thin and high cellular epidermis, acts as a barrier of the body that protects the body from external injuries and controls the loss of fluid during the injuries [169], the acellular dermis, usually consists of the collagen-rich extracellular matrix, providing the physical strength and flexibilities to the skin it accommodates the nerve bundles, vasculature, and lymphatic system [170, 171] and the inner layer of subcutaneous fat tissue is known as hypodermis that provides the thermal isolation and mechanical protection from outer injuries [169], as seen in Fig. 8.

Fig. 8
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Schematic representation of normal skin structure [169], which has three layers: epidermis, dermis, and hypodermis

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The skin has three layers of protection, yet it gets damaged due to different reasons such as injuries, reduced blood circulations, burns, and aging. These damages or injuries which disrupt the regular function and anatomic structure of skin are collectively defined as the wound [172]. Minor wounds can heal by themselves without additional treatment, whereas severe wounds require additional treatments to heal. Without proper treatment, during the major wounds, the skin’s integrity can be severely compromised and lead to deleterious outcomes such as morbidity and mortality [173].

Classification of Wounds

Healing time plays a crucial role in wound repair and injury management, and based on healing time, wounds can be classified into two major categories: (1) acute wounds and (2) chronic wounds [174]. The subcutaneous layers get compromised during the acute injuries due to the damage in the epidermis or superficial dermis region [175]. The main contributing factors for acute wounds are surgical incisions, thermal injuries, abrasions, and lacerations. In comparison, choric wounds are caused by specific diseases such as diabetes, tumors, and severe physical conditions [176], and chronic wounds reappear frequently [177]. Choric wounds usually take more than 12 weeks to heal [178], whereas acute wounds get cured within 8–12 weeks [179]. Apart from the healing process and time, wounds can be classified in four other ways based on appearances of injuries [177]. Another criterion for the wound classification is the number of affected layers and areas of wounded skin. Based on this criterion, it can be classified into three major types [172]. The overall classification of wounds is depicted in Fig. 9.

Fig. 9
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Wounds are categorized into three significant aspects, and those individual aspects have several other types of wounds

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Concept of Wound Healing

Correct and efficient wound healing is essential for the continuation of life. From the ancient time-efficient healing was a daunting task, which still poses a challenge for the physicians and scientists. The animal body consists of different tissues and organs, and any part of the body can experience wounds. Even though different body parts have different cell structures, most of the wounded cells or body parts heal following a similar pattern. From inception to heal, wound healing is a continuous process. However, for understanding purposes, the overall healing process was divided into several phases. Synchronized interactions between the different immunological and biological systems are a prerequisite for the successful recovery of a wound. Healing has a precise consecutive regulated step that correlates various cell types in the wound bed during the individual stages of healing. These steps are summarized into four consecutive events: (1) coagulation and hemostasis, starts right after any incident; (2) inflammation, right after earlier event, (3) proliferation, which begins within few days of the injury and comprehends the main healing progressions, and (4) wound remodeling, where the formation of scar tissue takes place. The last phase, wound remodeling, can last up to a year or more. Wound healing steps are schematically represented in Fig. 10. The coagulation and hemostasis primarily prevent the exsanguination. While preventing exsanguination, it protects the vascular system by keeping it intact, so vital organs’ function remains undamaged despite injury [174]. The inflammatory phase follows the hemostasis and takes approximately 24 h to form the injury to begin. Against invading micro-organisms, inflammation establishes a resistant barrier. Two separate phases constitute the entire inflammation stage: the early inflammatory phase and the late inflammatory phase [174]. The proliferation began roughly on the third day of wounding and continued for the next 2 weeks. During this phase, the wound gets covered by epithelium, and new granulating tissues are formed. Microphages, fibroblasts, and blood vessels come simultaneously near the wound bed and act as a single unit during this phase [177]. The remodeling phase is responsible for new epithelium and final scar tissue formation. Scar tissue formation can take 1–2 years or longer [174, 180]. In-depth healing mechanisms are beyond is the article’s scope, and interested readers can go through the following literature [174, 181, 182] to know the wound healing mechanism in detail.

Fig. 10
figure 10

Schematics of wound healing phases [186]. Hemostasis begins right after the injury, which is followed by the inflammation stage. Proliferation is the third phase of healing the injury and one of the key phases of wound healing. Finally, scar tissue formation takes place in the remodeling phase

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Required Properties for Ideal Dressing Materials

Wound healing treatment has been evolved significantly over time. However, the requirements for ideal healing remained similar. Selecting the appropriate dressing system based on the type of wound is the main requirement for good healing. Since its inception, different healing materials were used, which are broadly classified based on different criteria. Based on the source, frequently used wound dressing materials are categorized into three types [183]: (1) biologic, (2) synthetic, (3) biologic-synthetic composite. Every kind of dressing material has unique properties, which is why these sealants are applied to specific kinds of wounds. Irrespective application and categories, all the dressing materials should possess the some properties such as keep a suitable moist environment with exudates around the wound bed, allow gaseous exchange, remove excess exudates while acting as a barrier to microorganisms, free of infection, non-toxic, non-allergenic, non-sensitizing, fully biocompatible, easily removable from the wound site without any trauma, readily available with minimal processing time and cost, antimicrobial properties, thermal insulation, promotes wound healing and stimulate the growth factor [169, 177, 183] to be considered as good dressing material.

Biopolymers in Wound Healing

Biopolymers or natural polymers are the principal candidates for wound and burn healing. Natural polymers have extensive use in dressing a wound or burn injury due to their biocompatibility, biodegradability, and resemblance to ECM [184, 185]. The main sources of these organic healing materials are living organisms such as fungi (chitin), algae (alginate), bacteria (bacterial cellulose, exopolysaccharides), plant (starch, cellulose, and natural rubber), and animal (collagen, hyaluronic acid, chitosan) [186]. A sequence of repeating units held by different covalent bonds form these biopolymers, such as monomers of amino acids, nucleotides, monosaccharides, etc. held by covalent bonds form the biopolymer peptides, polyphenols, polysaccharides, or polyesters, etc. Because of the 3D network structure, these biopolymers can easily be saturated with water or biological fluids. These ingrained healing characteristics made them the active choice for pharmaceutical and biomedical applications, exclusively for wound healing, tissue engineering, drug delivery, and implants [187].

Collagen is one of the essential structural proteins of any organ and is mostly found in connective tissues. ECM and collagen have similar structural and functional characteristics, which further inspired the use of collagen matrices in wound healing applications. Chemically collagen has a triple helix fibril structure where a repeating amino acid polymer is held by peptide linkages. Collagen plays a pivotal role in natural healing, from the clotting induction to the development and appearance of the final scar. Fibroblast’s formation in damaged tissues is stimulated, and the migration of endothelial cells is accelerated once the damaged tissue gets in contact with collage. Knapp et al. [188] first reported the medical usage of external collagen in human. They prepared allogenic and xenogeneic source-based collagen, which further used a structural basis for soft tissues. Since then, twenty-nine types of collages were identified, and among those, I, II, and III types have extensive use in wound healing [186]. Bovine, porcine, and avian are the primary sources for natural or bio collagen dressing formulation [189]. Different forms of collagen have numerous biomedical applications in literature, and a few of the applications are tabulated in Table 7.

Table 7 Applications of collagen in wound healing
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Chitin is the second most used biopolymers in wound healing [196]. Chitins are inert polysaccharide copolymer and extracted from the invertebrates (crustacean shells or insect cuticles, mushroom envelopes, green algae cell walls, and yeasts). Chitosan is derived from chitin, which is the active and partial deacetylated form of chitin. Their biocompatibility, biodegradability, non-toxicity, antimicrobial, and hydrating properties made them ideal candidates for wound healing, especially for open and deep wound healing. These have the haemostatic effect that accelerates fibroblasts layer formation during the healing [168]. Chitin and chitosan were used with other polymers to make hydrogels, foams, scaffolds, etc. and these copolymers have extensive use in wound dressing applications (Table 8). The chitin and chitosan derived polymers are extensively used in wound healing; however, they are still expensive due to their handing issues [168].

Table 8 Chitin and chitosan-based biomaterials for various types of wound healing
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Cellulose is a plant-derived polymer and extensively used in wound healing. The repeating units of β-d-glucose connected by β-1, 4-glycosidic linkages formed the cellulose structure. Film obtained from the cellulose exhibits outstanding properties such as high purity, good tensile strength, high exudates capacity, biodegradability, and unique nanofibril morphology network structure [168]. Cellulose usually keeps wound moist and moist wounds heal more rapidly due to enough supply of growth factors and other nutrients to the healing tissues [185]. Along with these outstanding properties, cellulose-based films have some drawbacks, such as a lack of antibacterial protection in the wounded areas, restricting its extensive use as dressing materials [168]. Alginic acid is usually extracted from the brown algae and it comprises a linear copolymer of α-L-guluronic acid and β-D-mannuronic acid. Alginate absorbs the exudates while keeping the wound bed moist. They also reduce the pain, lower the infection, reduce the odor of the wound, most importantly, helps in hemostasis [204]. Initially, it was applied as a gel, whereas its recent uses were mostly seen as sponges. Hyaluronic acid protects an injured area from microorganisms by using its bacteriostatic property. The anti-inflammatory and pro-inflammatory properties are the characteristic features of high molecular weight and low molecular weight hyaluronan, respectively [185]. It helps in the remodeling of ECM and keratinocyte migration, it also plays a pivotal role in stimulating fibroblast proliferation. Gelatin is a collagen-derived protein. In skin tissue engineering, gelatin showed extensive epithelialization and granulation tissue formation [170]. Wound dressing hydrogel membranes were prepared by blending PVA with gelatin and those membranes showed a good result on fibroblast culture and proliferation. In addition to these reported biopolymers, some other natural polymers such as starch, fucoidan, glucan, dextran, keratin, and silk, etc., have shown decent assistance in wound healing. Exploring the full potential and capabilities of these materials in facilitating wound healing requires more detailed studies.

Miscellaneous Applications

Miscellaneous applications include various potential application areas of both natural and synthetic biopolymers such as biosensors, medical and hygiene fields. This section discusses these promising application areas of biopolymers.

Biosensor

Recent advancement of technology helps to explore the development of new electrochemical biosensor architectures broadly for healthcare monitoring [205]. Some of the most extensively studied polysaccharides in this field are chitosan and carboxymethyl cellulose [206, 207], due to their extraordinary properties include biodegradability, biocompatibility, non-toxicity, adherent thin films forming ability, renewable, and abundant in nature [208, 209]. Another kind of biopolymer, laccases at the enzyme’s active center contain copper atoms’ cluster known as glycoproteins, which transfer electrons during redox reactions, including the reduction of molecular oxygen to water and the oxidation in the reduced form of phenolic compounds [210]. Biosensors based on laccase permit phenolic compounds to be directly investigated in complex matrices because of their sensitivity and selectivity. They are also beneficial due to rapid responses and miniaturization possibility, simplicity of fabrication, low cost, potential ability for on-site and real-time analysis. Biosensors developed from laccase can be used in the indirect determination of drugs that refer to parallel reactions, which can occur in enzymatic reactions with substrate or product. Sartori et al. developed a voltametric sensor using polyphenol oxidase, an extract of sweet potato to investigate the presence of a sulfite in wine samples (Ipomoea batatas (L.) Lam.) [211]. Here sulfite acts as a nucleophile that reacts with o-quinone to form o-quinone sulfite. Biosensors can be used as suitable alternative strategies to develop precise, simple, and effective analytical methods for indirect determination of spironolactone in the treatment of critical hypertension, liver cirrhosis, and congestive heart failure [212].

Carbonaceous nanomaterials, such as multi-walled carbon nanotubes (MWCNTs), have been broadly used to modify surfaces of electrodes to develop new architectures of biosensors [208, 213]. These sensors exhibit a high potential to transport electric signals that are generated upon biological response recognition, which result from a biochemical reaction between the target analyte and the enzyme immobilized on the sensor surface. The small size MWCNTs enhances the electrochemical efficiency of bulk electrodes via promoting a high transmission electronic signal between the electrode/solution interfaces, thereby increasing the sensitivity and lowering the detection limits.

Medical and Hygiene

Biopolymers have significant usage for various medical applications for occlusion, suturing, covering, fixation, isolation, adhesion, cellular proliferation, controlled drug delivery, contact inhibition, tissue guide, etc (Table 9). Poly-(L-lactic acid), poly-(glyconic acid) and copolymers of them are widely used as sutures because they offer exceptional flexibility and reliant knot robustness [214, 215]. Poly(ortho ester) and poly-hydroxy groups are mostly used for drug delivery. Polyurethanes have flexible, robust, wear, and tear properties that are significant for grafting scaffold facilitating artificial blood vessels [216]. Polyesteramides which have good mechanical and thermal properties, are used to facilitate drug delivery, hydrogel, and tissue engineering application. Hospitals are primarily used hygiene and healthcare products such as surgical masks, gloves, surgical gowns, towels, sanitary napkins, diapers, bedding, surgical footwear and headwear, panties shields, antimicrobial textiles, surgical drapes, wipes, etc. which are both disposable and non-disposable. Biobased PET can be used for surgical gowns instead of conventional cotton, polyester, and polyethylene [217]. Polylactic acid is used for the purpose of making gowns, masks, and caps [218]. Thermoplastic starch is used for making baby diapers because of its super absorbent property [219]. Biomaterials, including alginate fibers, catgut, collagen, chitosan, and super absorbent polymer, are also used mainly for medical and hygiene applications. Table 10 presents the possible applications of biopolymers in the medical and hygiene fields.

Table 9 Applications of biopolymers in the medical field [214,215,216,217,218,219]
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Table 10 Possible biopolymer applications in the medical field [220]
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Summary and Future Perspectives

In this review, we presented the potential use of biopolymeric materials in the field of biomedical applications, which have found to be increased significantly to a great extent unambiguously by considering their characteristic properties, including mechanical, thermal, compatibility, optical, and so on, the most promising state-of-the-art processing methods for the fabrication of smart biopolymers along with an overview of the diverse applications in the biomedical fields. The various synthetic routes developed for preparing biopolymers during research findings are compiled, along with their significant parameters for multiple applications. Based on the research findings, it could be suggested that the development and improvement of various biopolymeric materials through functionalization or hybridization with different functionalities are very important for target-oriented biomedical applications. For example, the blending of biopolymers with other biodegradable polymers could be one of the best ways to prepare new polymeric systems with "tailor-made" functional properties such as physical properties and biodegradability. The preparation of bio nanocomposites is a promising method to enhance the polymeric properties while the final polymer can maintain biodegradability. Despite the much improvement made in the field of biomedicals by using biopolymers, significant studies should be carried out for making suitable drug delivery systems, which could be a more robust method with reliability. In addition, the knowledge of the mechanism and time taken for the drug delivery system for a tissue or cellular compartment in respect to objective is critical. These are the challenges to address the unresolved medical need over time.

Future advances in implementing various biopolymeric systems in therapeutics applications, including the capability to scale up with controlled and targeted properties, could be a significant step for the future as the proper nanocarrier is essential to carry the DNA or genetic material to the targeted site. Therefore, efficient processing methods for harvesting such biopolymeric systems need to be prioritized as they will be used more in biological systems. It could also be strongly suggested that computational models can be integrated to interpret the effects on the profile of the materials, such as degradation profile and intra- and extra-cellular trafficking of polymeric nanoparticles for increased commercialization. Therefore, intense research on the surface and functionalization of biopolymers such as nanocellulose is potentially required to bring a revolutionary breakthrough of biomedical materials because modification of either chemical or surface could significantly alter the cell-material interaction properties. This review has provided promising results from recent studies, which will open a new avenue for developing more advanced smart biopolymers with controlled functional properties, guiding a platform for designing more efficient biopolymers for biomedical applications.